Substituted cyclic amine metalloprotease inhibitors

ABSTRACT

The invention provides compounds which are useful as inhibitors of metalloproteases, and which are effective in treating conditions characterized by excess activity of these enzymes. In particular, the present invention relates to a compound having a structure according to Formula (I).  
                 
Also disclosed are compounds, pharmaceutical compositions and methods of treating diseases characterized by metalloprotease activity using these compounds or the pharmaceutical compositions containing them.

CROSS REFERENCE

This application claims priority under Title 35, United States Code119(e) from Provisional Application Ser. No. 60/024,842, filed Aug. 28,1996.

TECHNICAL FIELD

This invention is directed to compounds which are useful in treatingdiseases associated with metalloprotease activity, particularly zincmetalloprotease activity.

BACKGROUND

Background

A number of structurally related metalloproteases [MPs] effect thebreakdown of structural proteins. These metalloproteases often act onthe intercellular matrix, and thus are involved in tissue breakdown andremodeling. Such proteins are referred to as metalloproteases or MPs.There are several different families of MPs, classified by sequencehomology. Several families of known MPs, as well as examples thereof,are disclosed in the art.

These MPs include Matrix-Metallo Proteases [MMPs], zincmetalloproteases, many of the membrane bound metalloproteases, TNFconverting enzymes, angiotensin-converting enzymes (ACEs), disintegrins,including ADAMs (See Wolfsberg et al, 131 J. Cell Bio. 275-78 October,1995), and the enkephalinases. Examples of MPs include human skinfibroblast collagenase, human skin fibroblast gelatinase, human sputumcollagenase, aggrecanse and gelatinase, and human stromelysin.Collagenase, stromelysin, aggrecanase and related enzymes are thought tobe important in mediating the symptomatology of a number of diseases.

Potential therapeutic indications of MP inhibitors have been discussedin the literature. See for example, U.S. Pat. No. 5,506,242 (Ciba GeigyCorp.); U.S. Pat. No. 5,403,952 (Merck & Co.); PCT published applicationWO 96/06074 (British Bio Tech Ltd); PCT Publication WO 96/00214 (CibaGeigy); WO 95/35275 (British Bio Tech Ltd); WO 95/35276 (British BioTech Ltd); WO 95/33731 (Hoffman-LaRoche); WO 95/33709 (Hoffman-LaRoche);WO 95/32944 (British Bio Tech Ltd); WO 95/26989 (Merck); WO 9529892(DuPont Merck); WO 95/24921 (Inst. Opthamology); WO 95/23790 (SmithKlineBeecham); WO 95/22966 (Sanofi Winthrop); WO 95/19965 (Glycomed); WO 9519956 (British Bio Tech Ltd); WO 95/19957 (British Bio Tech Ltd); WO95/19961 (British Bio Tech Ltd) WO 95/13289 (Chiroscience Ltd); WO95/12603 (Syntex); WO 95/09633 (Florida State Univ); WO 95/09620(Florida State Univ.); WO 95/04033 (Celltech); WO 94/25434 (Celltech);WO 94/25435 (Celltech); WO 93/14112 (Merck); WO 94/0019 (Glaxo); WO93/21942 (British Bio Tech Ltd); WO 92/22523 (Res. Corp. Tech. Inc.); WO94/10990 (British Bio Tech Ltd); WO 93/09090 (Yamanouchi); and Britishpatents GB 2282598 (Merck) and GB 2268934 (British Bio Tech Ltd);Published European Patent Applications EP 95/684240 (Hoffman LaRoche);EP 574758 (Hoffman LaRoche); EP 575844 (Hoffman LaRoche); PublishedJapanese applications; JP 08053403 (Fujusowa Pharm. Co. Ltd.); JP7304770 (Kanebo Ltd.); and Bird et al J. Med Chem vol. 37, pp. 158-69(1994). Examples of potential therapeutic uses of MP inhibitors includerheumatoid arthritis (Mullins, D. E., et al., Biochim. Biophys. Acta.(1983) 695: 117-214); osteoarthritis (Henderson, B., et al., Drugs ofthe Future (1990) 15: 495-508); the metastasis of tumor cells (ibid,Broadhurst, M. J., et al., European Patent Application 276,436(published 1987), Reich, R., et al., 48 Cancer Res. 3307-3312 (1988);and various ulcerations or ulcerative conditions of tissue. For example,ulcerative conditions can result in the cornea as the result of alkaliburns or as a result of infection by Pseudomonas aeruginosa,Acanthamoeba, Herpes simplex and vaccinia viruses.

Other examples of conditions characterized by undesired metalloproteaseactivity include periodontal disease, epidermolysis bullosa, fever,inflammation and scleritis (Cf. DeCicco et al, WO 95 29892 publishedNov. 9, 1995).

In view of the involvement of such metalloproteases in a number ofdisease conditions, attempts have been made to prepare inhibitors tothese enzymes. A number of such inhibitors are disclosed in theliterature. Examples include U.S. Pat. No. 5,183,900, issued Feb. 2,1993 to Galardy; U.S. Pat. No. 4,996,358, issued Feb. 26, 1991 to Handa,et al.; U.S. Pat. No. 4,771,038, issued Sep. 13, 1988 to Wolanin, etal.; U.S. Pat. No. 4,743,587, issued May 10, 1988 to Dickens, et al.,European Patent Publication Number 575,844, published Dec. 29, 1993 byBroadhurst, et al.; International Patent Publication No. WO 93/09090,published May 13, 1993 by Isomura, et al.; World Patent Publication92/17460, published Oct. 15, 1992 by Markwell et al.; and EuropeanPatent Publication Number 498,665, published Aug. 12, 1992 by Beckett,et al.

Though a variety of inhibitors have been prepared, there is a continuingneed for potent matrix metalloprotease inhibitors useful in treatingsuch diseases. It would be advantageous to inhibit thesemetalloproteases as a method of treating diseases related to unwantedmetalloprotease activity. Though a variety of inhibitors have beenprepared, there is a continuing need for potent metalloproteaseinhibitors useful in treating such diseases.

OBJECTS OF THE INVENTION

It is an object of the invention to provide potent inhibitors ofmetalloproteases.

It is a further object of the invention to provide pharmaceuticalcompositons comprising such inhibitors.

It is also an object of the invention to provide a method of treatmentfor metalloprotease related maladies.

SUMMARY OF THE INVENTION

The invention provides compounds which are useful as inhibitors ofmetalloproteases, and which are effective in treating conditionscharacterized by excess activity of these enzymes. In particular, thepresent invention relates to a compound having a structure according toFormula (I)

wherein

-   -   Ar is alkyl, heteroalkyl, aryl or heteroaryl substituted or        unsubstituted;    -   R₁ is OH, alkoxy, NHOR₂, where R₂ is hydrogen or alkyl;    -   W is one or more of hydrogen, lower alkyl or an alkylene bridge;    -   Y is independently one or more of hydroxy, SR₃, SOR₄, SO₂R₅,        alkoxy, amino, wherein amino is of formula NR₆R₇, wherein R₆ and        R₇ are independently chosen from hydrogen, alkyl, heteroalkyl,        heteroaryl, aryl, OR₃, SO₂R₈, COR₉, CSR₁₀, PO(R₁₁)₂; and    -   R₃ is hydrogen, alkyl, aryl, heteroaryl;    -   R₄ is alkyl, aryl, heteroaryl;    -   R₈ is alkyl, aryl, heteroaryl heteroalkyl, amino, alkylamino,        dialkylamino, arylamino, diarylamino and alkylarylamino;    -   R₉ is hydrogen, alkoxy, aryloxy, heteroaryloxy, alkyl, aryl,        heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino,        arylamino and alkylarylamino;    -   R₁₀ is alkyl aryl, heteroaryl, heteroalkyl, amino, alkylamino,        dialkylamino, arylamino, diarylamino and alkylarylamino;    -   R₁₁ is alkyl, aryl, heteroaryl, heteroalkyl;    -   Z is hydrogen, hydroxy, alkyl alkylene or heteroalkylene;    -   n is 1-3.

This structure also includes an optical isomer, diastereomer orenantiomer for Formula (I), or a pharmaceutically-acceptable salt, orbiohydrolyzable amide, ester, or imide thereof.

These compounds have the ability to inhibit at least one mammalianmatrix metalloprotease. Accordingly, in other aspects, the invention isacted to pharmaceutical compositions containing the compounds of Formula(I), and to methods of treating diseases characterized bymetalloprotease activity using these compounds or the pharmaceuticalcompositions containing them.

Applicants have found that compounds of Formula (I) are potentinhibitors of metalloproteases. The compounds of the present inventiontherefore are useful for the treatment of conditions and diseases whichare characterized by unwanted activity by the class of proteins whichdestroy structural proteins.

Metalloproteases active at a particularly undesired location (e.g., anorgan or certain types of cells) can be targeted by conjugating thecompounds of the invention to a targeting ligand specific for a markerat that location such as an antibody or fragment thereof or a receptorligand. Conjugation methods are known in the art.

The invention is also directed to various other processes which takeadvantage of the unique properties of these compounds. Thus, in anotheraspect, the invention is directed to the compounds of Formula (I)conjugated to solid supports. These conjugates can be used as affinityreagents for the purification of a desired metalloprotease.

In another aspect, the invention is directed to the compounds of Formula(I) conjugated to label. As the compounds of the invention bind to atleast one metalloprotease, the label can be used to detect the presenceof relatively high levels of metalloprotease in vivo or in vitro cellculture.

In addition, the compounds of Formula (I) can be conjugated to carrierswhich permit the use of these compounds in immunization protocols toprepare antibodies specifically immunoreactive with the compounds of theinvention. Typical conjugation methods are known in the art. Theseantibodies are then useful both in therapy and in monitoring the dosageof the inhibitors.

DETAILED DESCRIPTION

The compounds of the present invention are inhibitors of mammalianmetalloproteases. Preferably, the compounds are those of Formula (I) ora pharmaceutically-acceptable set, or biohydrolyzable amide, ester, orimide thereof.

Definitions and Usage of Terms:

The following is a list of definitions for terms used herein:

“Acyl” or “carbonyl” is described as a radical which could be formed byremoval of the hydroxy from a carboxylic acid (i.e., R—C(═O)—).Preferred acyl groups include (for example) acetyl, formyl, andpropionyl.

“Acyloxy” is an oxy radical having an acyl substituent (i.e., —O-acyl);for example, —O—C(═O)-alkyl.

“Alkoxyacyl” is an acyl radical (—C(═O)—) having an alkoxy substituent(i.e., —O—R), for example, —C(═O)O-alkyl. This radical can be referredto as an eater.

“Acylamino” is an amino radical having an acyl substituent (i.e.,—N-acyl); for example, —NH—C(═O)-alkyl.

“Alkenyl” is an unsubstituted or substituted hydrocarbon chain radicalhaving 2 to 15 carbon atoms; preferably from 2 to 10 carbon atoms; morepreferably from 2 to 8; except where indicated. Alkenyl substituentshave at least one olefinic double bond (including, for example, vinyl,allyl and butenyl).

“Alkynyl” is an unsubstituted or substituted hydrocarbon chain radicalhaving 2 to 15 carbon atoms; preferably from 2 to 10 carbon atoms; morepreferably from 2 to 8; except where indicated. The chain has at leastone carbon-carbon triple bond.

“Alkoxy” is an oxygen radical having a hydrocarbon chain substituent,where the hydrocarbon chain is an alkyl or alkenyl (i.e., —O-alkyl or—O-alkenyl). Preferred alkoxy groups include (for example) methoxy,ethoxy, propoxy and allyloxy.

“Alkoxyalkyl” is an unsubstituted or substituted alkyl moietysubstituted with an to alkoxy moiety (i.e., -alkyl-O-alkyl). Preferredis where the alkyl has 1 to 6 carbon atoms (more preferably 1 to 3carbon atoms), and the alkyoxy has 1 to 6 carbon atoms (more preferably1 to 3 carbon atoms).

“Alkyl” is an unsubstituted or substituted saturated hydrocarbon chainradical having 1 to 15 carbon atoms; preferably from 1 to 10 carbonatoms; more preferably 1 to 4; except where indicated. Preferred alkylgroups include (for example) substituted or unsubstituted methyl, ethyl,propyl, isopropyl, and butyl.

Alkylene refers to an alkyl, alkenyl or alkynyl which is diradical,rather than a radical. “Hetero alkylene” is likewise defined as a(diradical) alkylene having a heteroatom in its chains hence an“alkylene bridge” is a hydrocarbon diradical that attaches to twodifferent carbons (hence making a bicyclic structure), prefered alkylenebridges include methylene, ethylene and propylene.

“Alkylamino” is an amino radical having one (secondary amine) or two(tertiary amine) alkyl substituents (i.e., —N-alkyl). For example,methylamino (—NHCH₃), dimethylamino (—N(CH₃)₂), methylethylamino(—N(CH₃)CH₂CH₃).

“Aminoacyl” is acyl radical having an amino substituent (i.e.,—C(═O)—N); for example, —C(═O)—NH₂. The amino group of the aminoacylmoiety may be unsubstituted (i.e., primary amine) or may be substitutedwith one (secondary amine) or two (i.e., tertiary amine) alkyl groups.

“Aryl” is an aromatic carbocyclic ring radical. Preferred aryl groupsinclude (for example) phenyl, tolyl, xylyl, cumenyl and naphthyl.

“Arylalkyl” is an alkyl radical substituted with an aryl group.Preferred arylalkyl groups include benzyl, phenylethyl and phenylpropyl.

“Arylalkylamino” is an amine radical substituted with an arylalkyl group(e.g., —NH-benzyl).

“Arylamino” is an amine radical substituted with an aryl group (i.e.,—NH-aryl).

“Aryloxy” is an oxygen radical having an aryl substituent (i.e.,—O-aryl).

“Carbocyclic ring” is an unsubstituted or substituted, saturated,unsaturated or aromatic, hydrocarbon ring radical. Carbocyclic rings aremonocyclic or are fused, bridged or spiro polycyclic ring systems.Monocyclic carbocyclic rings generally contain 4 to 9 atoms, preferably4 to 7 atoms. Polycyclic carbocyclic rings contain 7 to 17 atoms,preferably from 7 to 12 atoms. Preferred polycyclic systems comprise 4-,5-, 6- or 7-membered rings fused to 5-, 6-, or 7-membered rings.

“Carbocycle-alkyl” is an unsubstituted or substituted alkyl radicalsubstituted with a carbocyclic ring. Unless otherwise specified, thecarbocyclic ring is preferably an aryl or cycloalkyl; more preferably anaryl. Preferred carbocycle-alkyl groups include benzyl, phenylethyl andphenylpropyl.

“Carbocycle-heteroalkyl” is an unsubstituted or substituted heteroalkylradical substituted with a carbocyclic ring. Unless otherwise specified,the carbocyclic ring is preferably an aryl or cycloalkyl; morepreferably an aryl. The heteroalkyl is preferably 2-oxa-propyl,2-oxa-ethyl, 2-thia-propyl, or 2-thia-ethyl.

“Carboxyalkyl” is an unsubstituted or substituted alkyl radicalsubstituted with with a carboxy (—C(═O)OH) moiety. For example,—CH₂—C(O)OH.

“Cycloalkyl” is a saturated carbocyclic ring radical. Preferredcycloalkyl groups include (for example) cyclopropyl, cyclobutyl andcyclohexyl.

“Cycloheteroalkyl” is a saturated heterocyclic ring. Preferredcycloheteroalkyl groups include (for example) morpholinyl, piperadinyl,and piperazinyl.

“Fused rings” are rings that are superimposed together such that theyshare two ring atoms. A given ring may be fused to more than one otherring. Fused rings are contemplated in heteroaryl; aryl and heterocycleradicals or the like.

“Heterocycle-alkyl” is an alkyl radical substituted with a heterocyclicring. The heterocyclic ring is preferably an heteroaryl orcycloheteroalkyl; more preferably an heteroaryl. Preferred heterocyclealkyl include C₁-C₄ alkyl having preferred heteroaryl appended to them.More preferred is, for example, pyridyl alkyl, and the like.

“Heterocycle-heteroalkyl” is an unsubstituted or substituted heteroalkylradical substituted with a heterocyclic ring. The heterocyclic ring ispreferably an aryl or cycloheteroalkyl; more preferably an aryl.

“Heteroatom” is a nitrogen, sulfur or oxygen atom. Groups containing oneor more heteroatoms may contain different heteroatoms.

“Heteroalkenyl” is an unsubstituted or substituted unsaturated chainradical having 3 to 8 members comprising carbon atoms and one or twoheteroatoms. The chain has at least one carbon-carbon double bond.

“Heteroalkyl” is an unsubstituted or substituted saturated chain radicalhaving 2 to 8 comprising carbon atoms and one or two heteroatoms.

“Heterocyclic ring” is an unsubstituted or substituted, saturated,unsaturated or aromatic ring radical comprised of carbon atoms and oneor more heteroatoms in the ring. Heterocyclic rings are monocyclic orare fused, bridged or spiro polycyclic ring systems. Monocyclicheterocyclic rings contain 3 to 9 atoms, preferably 4 to 7 atoms.Polycyclic rings contain 7 to 17 atoms, preferably from 7 to 13 atoms.

“Heteroaryl” is an aromatic heterocyclic ring, either monocyclic orbicyclic radical. Preferred heteroaryl groups include (for example)thienyl, furyl, pyrrolyl, pyridinyl, pyrazinyl, thiazolyl, pyrimidinyl,quinolinyl, and tetrazolyl, benzo thiazolyl, benzofuryl, indolyl and thelike.

“Halo”, “halogen”, or “halide” includes chloro, bromo, fluoro or iodo,preferably chloro and fluoro.

Also, as referred to herein, a “lower” hydrocarbon moiety (e.g., “lower”alkyl) is a hydrocarbon chain comprised of 1 to 6, preferably from 1 to4, carbon atoms.

A “pharmaceutically-acceptable salt” is a cationic salt formed at anyacidic (e.g., is carboxyl) group, or an anionic salt formed at any basic(e.g., amino) group. Many such salts are known in the art, as describedin World Patent Publication 87/05297, Johnston et al., published Sep.11, 1987 (incorporated by reference herein). Preferred cationic saltsinclude the alkali metal salts (such as sodium and potassium), andalkaline earth metal salts (such as magnesium and calcium) and organicsalts. Preferred anionic salts include the halides (such as chloridesalts). Such salts are well understood by the skilled artisan, and theskilled artisan is able to prepare any number fo salts given theknowledge in the art. Furthermore, it is recognized that the skilledartisan may prefer one salt over another for reasons of solubility,stability, formulation ease and the like. Determination and optimizationof of such salts is within the purview of the skilled artisan'spractice.

“Biohydrolyzable amides” are amides of a metalloprotease inhibitor thatdo not interfere with the inhibitory activity of the compound, or thatare readily converted in vivo by an animal, preferably a mammal, morepreferably a human subject to yield an active metalloprotease inhibitor.

A “biohydrolyzable hydroxy imide” is an imide of a Formula (I) compoundthat does not interfere with the metalloprotease inhibitory activity ofthese compounds, or that is readily converted in vivo by an animal,preferably a mammal, more preferably a human subject to yield an activeFormula (I) compound.

A “biohydrolyzable ester” refers to an ester of a Formula (I) compoundthat does not interfere with the metalloprotease inhibitory activity ofthese compounds or that is readily converted by an animal to yield anactive Formula (I) compound.

A “solvate” is a complex formed by the combination of a solute (e.g., ametalloprotease inhibitor) and a solvent (e.g., water). See J. Honig etal., The Van Nostrand Chemist's Dictionary, p. 650 (1953).Pharmaceutically-acceptable solvents used according to this inventioninclude those that do not interfere with the biological activity of themetalloprotease inhibitor (e.g., water, ethanol, acetic acid,N,N-dimethylformamide and others known or readily determined by theskilled artisan).

“Optical isomer”, “stereoisomer”, “diastereomer” as referred to hereinhave the standard art recognized meanings (Cf., Hawley's CondensedChemical Dictionary, 11th Ed.).

The illustration of specific protected forms and other derivatives ofthe Formula (I) compounds is not intended to be limiting. Theapplication of other useful protecting groups, salt forms, etc. iswithin the ability of the skilled artisan.

As defined above and as used herein, substituent groups may themselvesbe substituted. Such substitution may be with one or more substituents.Such substituents include those listed in C. Hansch and A. Leo,Substituent Constants for Correlation Analysis in Chemistry and Biology(1979), incorporated by reference herein. Preferred substituents include(for example) alkyl, alkenyl, alkoxy, hydroxy, oxo, nitro, amino,aminoalkyl (e.g., aminomethyl, etc.), cyano, halo, carboxy, alkoxyaceyl(e.g., carboethoxy, etc.), thiol, aryl, cycloalkyl, heteroaryl,heterocycloalkyl (e.g., piperidinyl, morpholinyl, pyrrolidinyl, etc.),imino, thioxo, hydroxyalkyl, aryloxy, arylalkyl, and combinationsthereof.

As used herein, “mammalian metalloprotease” refers to the proteasesdisclosed in the “Background” of this application. Prefered “mammalianmetalloproteases” include any metal-containing (preferablyzinc-containing) enzyme found in animal, preferably mammalian sourcescapable of catalyzing the breakdown of collagen, gelatin or proteoglycanunder suitable assay conditions. Appropriate assay conditions can befound, for example, in U.S. Pat. No. 4,743,587, which references theprocedure of Cawston, et al., Anal. Biochem. (1979) 99: 340-345, use ofa synthetic substrate is described by Weingarten, H., et al., Biochem.Biophy. Res. Comm. (1984) 139: 1184-1187. Any standard method foranalyzing the breakdown of these structural proteins can, of course, beused. More prefered metalloprotease enzymes are zinc-containingproteases which are similar in structure to, for example, humanstromelysin or skin fibroblast collagenase. The ability of candidatecompounds to inhibit metalloprotease activity can, of course, be testedin the assays described above. Isolated metalloprotease enzymes can beused to confirm the inhibiting activity of the invention compounds, orcrude extracts which contain the range of enzymes capable of tissuebreakdown can be used.

Compounds:

Compounds of the invention are described in the Summary of theInvention, more preferred compounds of Formula (I) include,

wherein

-   -   Ar is aryl or heteroaryl, substituted or unsubstituted;    -   R₁ is OH, alkoxy, NHOR₂, where R₂ is hydrogen or alkyl;    -   W is one or more of hydrogen, lower alkyl;    -   Y is independently one or more of hydroxy, SR₃, SOR₄, SO₂R₅,        alkoxy, amino, wherein amino is of formula NR₆,R₇, wherein R₆        and R₇ are independently chosen from hydrogen, alkyl        heteroalkyl, heteroaryl aryl OR₃, SO₂R₈, COR₉, CSR₁₀, PO(R₁₁)₂;        and    -   R₃ is hydrogen, alkyl, aryl heteroaryl;    -   R₄ is alkyl, aryl, heteroaryl;    -   R₈ is alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino,        dialkylamino, arylamino, diarylamino and alkylarylamino;    -   R₉ is hydrogen, alkoxy, aryloxy, heteroaryloxy, alkyl, aryl,        heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino,        arylamino and alkylarylamino;    -   R₁₀ is alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino,        dialkylamino, arylamino, diarylamino and alkylarylamino;    -   R₁₁ is alkyl, aryl, heteroaryl, heteroalkyl;    -   Z is hydrogen;    -   n is 1-3.

There may be one or more W, Y and Z moeities on the molecule of theinvention. Preferably there are five or less substituents chosen from W,Y and Z which are not hydrogen. Y and Z moieties may appear on the samecarbon, i.e., geminal in relation to each other.

Where Z is heteroalkylene, it is prefered that heteroatoms adjacent tothe parent ring structure, more preferably such heteroalkyls have 2 to 4members. Perferred heteroatoms are divalent.

Preferred Ar include aryl and alkyl moieties. When Ar is aryl, itincludes heterocyclic and carbocyclic aryl either monocyclic orpolyciclic, preferably monocyclic aryl, more preferably phenyl; When Aris alkyl, it is preferably C₁ to C₁₈ alkyl, more preferably C₂ to C₈alkyl or heteroalkyl. Ar can be substituted or unsubstituted.

W is preferably a C₁ to C₄ alkyl or C₁ to C₄ alkylene bridge. When W isan alkylene bridge, it is preferably methylene, ethylene or propylene,more preferably methylene. When W is alkyl it is preferably methyl orethyl, more preferably methyl.

The variable “n” alters the size of the nitrogen containing ring, morepreferred ring sizes are 5 and 6 membered rings.

Compound Preparation:

The hydroxamic compounds of Formula (I) can be prepared using a varietyof procedures.

The starting materials used in preparing the compounds of the inventionare known, made by known methods, or are commercially available as astarting material. General schemes and representative examples of thepreparation of compounds of the invention follow.

In the following scheme W and Z are omitted for clarity. The skilledartisan will appreciate that Z may be added using similar methodologiesor those known in the art. W may be added by art to recognizedmethodologies as well. For compounds where Y is not adjacent to the ringnitrogen, a preferred method of making the compounds is;

Where R is a derivatizable group or can be manipulated or substituted,such compounds are known or are prepared by known methods. For example,when R is OH, and n is 1, hydroxyproline (A) is converted to itsanalogous sultamester and the hydroxyl is then manipulated to give (B)during this or a subsequent step Y and Z can be added or altered,followed by treatment with hydroxyl amine under basic conditions to give(C).

R′ may be a protecting group, a free acid or any moiety the skilledartisan prefers, provided that ultimately it provides the compounds ofthe invention.

A variety of compounds can be generated in a similar fashion, using theguidance of the scheme above.

It is recognized that it is preferable to use a protecting group for anyreactive functionality such as a carboxyl, hydroxyl and the like, duringthe formation of the sultameter. This is standard practice, well withinthe normal practice of the skilled artisan.

In the above schemes, where R is alkoxy or alkylthio, the correspondinghydroxy or thiol compounds are derived from the final compounds by usinga standard dealkylating procedure (Bhatt, et al., “Cleavage of Ethers”,Synthesis, 1983, pp. 249-281).

These steps may be varied to increase yield of desired product. Theskilled artisan will recognize the judicious choice of reactants,solvents, and temperatures is an important component in any successfulsynthesis. Determination of optimal conditions, etc. is routine. Thusthe skilled artisan can make a variety of compounds using the guidanceof the scheme above.

It is recognized that the skilled artisan in the art of organicchemistry can readily carry out standard manipulations of organiccompounds without further direction; that is, it is well within thescope and practice of the skilled artisan to carry out suchmanipulations. These include, but are not limited to, reduction ofcarbonyl compounds to their corresponding alcohols, oxidations ofhydroxyls and the like, acylations, aromatic substitutions, bothelectrophilic and nucleophilic, etherifications, esterification andsaponification and the like. Examples of these manipulations arediscussed in standard texts such as March, Advanced Organic Chemistry(Wiley), Carey and Sundberg, Advanced Organic Chemistry (Vol. 2) andother art that the skilled artisan is aware of.

The skilled artisan will readily appreciate that certain reactions arebest carried out when other potentially reactive functionality on themolecule is masked or protected, thus avoiding any undesirable sidereactions and/or increasing the yield of the reaction. Often the skilledartisan utilizes protecting groups to accomplish such increased yieldsor to avoid the undesired reactions. These reactions are found in theliterature and are also well within the scope of the skilled artisan.Examples of many of these manipulations can be found for example in T.Greene, Protecting Groups in Organic Synthesis. Of course, amino acidsused as starting materials with reactive side chains are preferablyblocked to prevent undesired side reactions.

The compounds of the invention may have one or more chiral centers. As aresult, one may selectively prepare one optical isomer, includingdiastereomer and enantiomer, over another, for example by chiralstarting materials, catalysts or solvents, or may prepare bothstereoisomers or both optical isomers, including diastereomers andenantiomers at once (a racemic mixture). Since the compounds of theinvention may exist as racemic mixtures, mixtures of optical isomers,including diastereomers and enantiomers, or stereoisomers may beseparated using known methods, such as chiral salts, chiralchromatography and the like.

In addition, it is recognized that one optical isomer, includingdiastereomer and enantiomer, or stereoisomer may have favorableproperties over the other. Thus when disclosing and claiming theinvention, when one racemic mixture is disclosed, it is clearlycontemplated that both optical isomers, including diastereomers andenantiomers, or stereoisomers substantially free of the other aredisclosed and claimed as well.

Methods of Use

Metalloproteases (MPs) found in the body operate, in part, by breakingdown the extracellular matrix, which comprises extracellular proteinsand glycoproteins. These proteins and glycoproteins play an importantrole in maintaining the size, shape, structure and stability of tissuein the body. Inhibitors of metalloproteases are useful in treatingdiseases caused, at least in part, by breakdown of such proteins. It isknown that MPs are intimately involved in tissue remodeling. As a resultof this activity they have been said to be active in many disordersinvolving either the:

-   -   breakdown of tissues; including degenerative diseases, such as        arthritis, multiple sclerosis and the like; metastasis or        mobility of tissues in the body:    -   the remodeling of tissues, including fibrotic disease, scarring,        benign hyperplasia, and the like.        The compounds of the present invention treat disorders, diseases        and/or unwanted conditions which are characterized by unwanted        or elevated activity by that class of proteases. For example the        compounds can be used to inhibit proteases which    -   destroy structural proteins (i.e. the proteins that maintain        tissue stability and structure);    -   interfere in inter/intracellular signaling, including those        implicated in cytokine up-regulation, and/or cytokine processing        and/or inflammation, tissue degradation and other maladies        [Mohler K M, et al, Nature 370 (1994) 218-220, Gearing A J H, et        al, Nature 370 (1994) 555-557 McGeehan G M, et al, Nature        370 (1994) 558-561], and/or    -   facilitate processes which are undesired in the subject being        treated, for example, the processes of sperm maturation, egg        fertilization and the like.

As used herein, a “MP related disorder” or “a MP related disease” is onethat involves unwanted or elevated MP activity in the biologicalmanifestation of the disease or disorder; in the biological cascadeleading to the disorder; or as a symptom of the disorder. This“involvement” of the MP includes;

-   -   The unwanted or elevated MP activity as a “cause” of the        disorder or biological manifestation, whether the activity was        elevated genetically, by infection, by autoimmunity, trauma,        biomechanical causes, lifestyle [e.g. obesity] or by some other        cause;    -   The MP as part of the observable manifestation of the disease or        disorder. That is, the disease or disorder is measurable in        terms of the increased MP activity, or from a clinical        standpoint, unwanted or elevated MP levels indicate the disease.        MPs need not be the “hallmark” of the disease or disorder;    -   The unwanted or elevated MP activity is part of the biochemical        or cellular cascade that results or relates to the disease or        disorder. In this respect, inhibition of the MP activity        interrupts the cascade, and thus controls the disease.

Advantageously, many MPs are not distributed evenly throughout the body.This the distribution of MPs expressed in various tissues are oftenspecific to those tissue. For example, the distribution ofmetalloproteases implicated in the breakdown of tissues in the joints,is not the same as the distribution of metalloproteases found in otherissues. Thus, though not essential for activity or efficacy, certaindisorders preferably are treated with compounds that act on specific MPsfound in the affected tissues or regions of the body. For example, acompound which displays a higher degree of affinity and inhibition for aMP found in the joints (e.g. chondrocytes) would be preferred fortreatment of disease found there than other compounds which are lessspecific.

In addition, certain inhibitors are more bioavialable to certain tissuesthan others, and this judicious choice of inhibitor, with theselectivity described above provides for specific treatment of thedisorder, disease or unwanted condition. For example, compounds of thisinvention vary in their ability to penetrate into the central nervoussystem. Thus compounds may be selected to produce effects mediatedthrough MPs found specifically outside the central nervous system.

Determination of the specificity of a MP inhibitor of a certain MP iswithin the skill of the artisan in that field. Appropriate assayconditions can be found in the literature. Specifically assays are knownfor stromelysin and collagenase. For example, U.S. Pat. No. 4,743,587references the procedure of Cawston, et al., Anal Biochem (1979) 99:340-345. The use of a synthetic substrate in an assay is described byWeingarten, H., et al., Biochem Biophy Res Comm (1984) 139: 1184-1187.Any standard method for analyzing the breakdown of structural proteinsby MPs can, of course, be used. The ability of compounds of theinvention to inhibit metalloprotease activity can, of course, be testedin the assays found in the literature, or variations thereof. Isolatedmetalloprotease enzymes can be used to confirm the inhibiting activityof the invention compounds, or crude extracts which contain the range ofenzymes capable of tissue breakdown can be used.

As a result of the MP inhibitory effect of the compounds of theinvention, the compounds of the invention are also useful in treatingthe following disorders by virtue of their metalloprotease activity.

The compounds of this invention are also useful for the prophylactic oracute treatment. They are administered in any way the skilled artisan inthe fields of medicine or pharmacology would desire. It is immediatelyapparent to the skilled artisan that preferred routes of administrationwill depend upon the disease state being treated, and the dosage formchosen. Preferred routes for systemic administration includeadministration perorally or parenterally.

However, the skilled artisan will readily appreciate the advantage ofadministering the MP inhibitor directly to the affected area for manydisorders. For example, it may be advantageous to administer MPinhibitors directly to the area of the disease or condition as in areaaffected by surgical trauma (e.g., angioplasty), area affected byscarring or burn (e.g., topical to the skin).

Because the remodeling of bone involves MPs, the compounds of theinvention are useful in preventing prosthesis loosening. It is known inthe art that over time prostheses loosen, become painful, and may resultin further bone injury, thus demanding replacement. The need forreplacement of such prostheses includes those such as in, jointreplacements (for example hip, knee and shoulder replacements), dentalprosthesis, including dentures, bridges and prosthesis secured to themaxilla and/or mandible.

MPs are also active in remodeling of the cardiovascular system (forexample, in congestive heart failure). It has been suggested that one ofthe reasons angioplasty has a higher than expected long term failurerate (reclosure over time) is that MP activity is not desired or iselevated in response to what may be recognized by the body as “injury”to the basement membrane of the vessel. Thus regulation of MP activityin indications such as dilated cardiomyopathy, congestive heart failure,atherosclerosis, plaque rupture, reperfusion injury, ischemia, chronicobstructive pulmonary disease, angioplasty restenosis and aorticaneurysm may increase long term success of any other treatment, or maybe a treatment in itself.

In skin care, MPs are implicated in the remodeling or “turnover” ofskin. As a result, the regulation of MPs improves treatment of skinconditions including but not limited to, wrinkle repair, regulation andprevention and repair of ultraviolet induced skin damage. Such atreatment includes prophylactic treatment or treatment before thephysiological manifestations are obvious. For example, the MP may beapplied as a pre-exposure treatment to prevent ultraviolet damage and/orduring or after exposure to prevent or minimize post-exposure damage. Inaddition, MPs are implicated in skin disorders and diseases related toabnormal tissues that result from abnormal turnover, which includesmetalloprotease activity, such as epidermolysis bullosa, psoriasis,scleroderma and atopic dermatitis. The compounds of the invention arealso useful for treating the consequences of “normal” injury to the skinincluding scarring or “contraction” of tissue, for example, followingburns. MP inhibition is also useful in surgical procedures involving theskin for prevention of scarring, and promotion of normal tissue growthincluding in such applications as limb reattachment and refractorysurgery (whether by laser or incision).

In addition, MPs are related to disorders involving irregular remodelingof other tissues, such as bone, for example, in otosclerosis and/orosteoporosis, or for specific organs, such as in liver cirrhosis andfibrotic lung disease. Similarly in diseases such as multiple sclerosis,MPs may be involved in the irregular modeling of blood brain barrierand/or myelin sheaths of nervous tissue. Thus regulating MP activity,may be used as a strategy in treating, preventing, and controlling suchdiseases.

MPs are also thought to be involved in many infections, includingcytomegalovirus; [CMV] retinitis; HIV, and the resulting syndrome, AIDS.

MPs may also be involved in extra vascularization where surroundingissue needs to be broken down to allow new blood vessels such as inangiofibroma and hemangioma.

Since MPs break down the extracellular matrix, it is contemplated thatinhibitors of these enzymes can be used as birth control agents, forexample in preventing ovulation, in preventing penetration of the sperminto and through the extracellular milieu of the ovum, implantation ofthe fertilized ovum and in preventing sperm maturation.

In addition they are also contemplated to be useful in preventing orstopping premature labor and delivery.

Since MPs are implicated in the inflammatory response, and in theprocessing of cytokines the compounds are also useful asanti-inflammatories, for use in disease where inflammation is prevalentincluding, inflammatory bowel disease, Crohn's disease, ulcerativecolitis, pancreatitis, diverticulitis, asthma or related lung disease,rheumatoid arthritis, gout and Reiter's Syndrome.

Where autoimmunity is the cause of the disorder, the immune responseoften triggers MP and cytokine activity. Regulation of MPs in treatingsuch autoimmune disorders is a useful treatment strategy. Thus MPinhibitors can be used for treating disorders including, lupuserythmatosis, ankylosing spondylitis, and autoimmune keratitis.Sometimes the side effects of autoimmune therapy result in exacerbationof other conditions mediated by MPs, here MP inhibitor therapy iseffective as well, for example, in autoimmune-therapy-induced fibrosis.

In addition, other fibrotic diseases lend themselves to this type oftherapy, including pulmonary disease, bronchitis, emphysema, cysticfibrosis, acute respiratory distress syndrome (especially the acutephase response).

Where MPs are implicated in the undesired breakdown of tissue byexogenous agents, these can be treated with MP inhibitors. For example,they are effective as rattle snake bite antidote, as anti-vessicants, intreating allergic inflammation, septicemia and shock. In addition, theyare useful as antiparasitics (e.g., in malaria) and antiinfectives. Forexample, they are thought to be useful in treating or preventing viralinfection, including infection which would result in herpes, “cold”(e.g., rhinoviral infection), meningitis, hepatitis, HIV infection andAIDS.

MP inhibitors are also thought to be useful in treating Alzheimer'sdisease, amyotrophic lateral sclerosis (ALS), muscular dystrophy,complications resulting from or arising out of diabetes, especiallythose involving loss of tissue viability, coagulation, Graft vs. Hostdisease, leukemia, cachexia, anorexia, proteinuria, and perhapsregulation of hair growth.

For some diseases, conditions or disorders MP inhibition is contemplatedto be a preferred method of treatment. Such diseases, conditions ordisorders include, arthritis (including osteoarthritis and rheumitoidarthritis), cancer (especially the prevention or arrest of tumor growthand metastasis), ocular disorders (especially corneal ulceration, lackof corneal healing, macular degeneration, and pterygium), and gumdisease (especially periodontal disease, and gingivitis).

Compounds preferred for, but not limited to, the treatment of arthritis(including osteoarthritis and rheumatoid arthritis) are those compoundsthat are selective for the matrix metalloproteases and the disintegrinmetalloproteases.

Compounds preferred for, but not limited to, the treatment of cancer(especially the prevention or arrest of tumor growth and metastasis) arethose compounds that preferentially inhibit gelatinases or type IVcollagenases.

Compounds preferred for, but not limited to, the treatment of oculardisorders (especially corneal ulceration, lack of corneal healing,macular degeneration, and pterygium) ar those compounds that broadlyinhibit metalloproteases. Preferably these compounds are administeredtopically, more preferably as a drop or gel.

Compounds preferred for, but not limited to, the treatment of gumdisease (especially periodontal disease, and gingivitis) are thosecompounds that preferentially inhibit collagenases.

Compositions:

The compositions of the invention comprise:

-   -   (a) a safe and effective amount of a compound of Formula (I);        and    -   (b) a pharmaceutically-acceptable carrier.

As discussed above, numerous diseases are known to be mediated by excessor undesired metalloprotease activity. These include tumor metastasis,osteoarthritis, rheumatoid arthritis, skin inflammation, ulcerations,particularly of the cornea, reaction to infection, periodontitis and thelike. Thus, the compounds of the invention are useful in therapy withregard to conditions involving this unwanted activity.

The invention compounds can therefore be formulated into pharmaceuticalcompositions for use in treatment or prophylaxis of these conditions.Standard pharmaceutical formulation techniques are used, such as thosedisclosed in Remington's Pharmaceutical Sciences, Mack PublishingCompany, Easton, Pa., latest edition.

A “safe and effective amount” of a Formula (I) compound is an amountthat is effective, to inhibit metalloproteases at the site(s) ofactivity, in an animal, preferably a mammal, more preferably a humansubject, without undue adverse side effects (such as toxicity,irritation, or allergic response), commensurate with a reasonablebenefit/risk ratio when used in the manner of this invention. Thespecific “safe and effective amount” will, obviously, vary with suchfactors as the particular condition being treated, the physicalcondition of the patient, the duration of treatment, the nature ofconcurrent therapy (if any), the specific dosage form to be used, thecarrier employed, the solubility of the Formula (I) compound therein,and the dosage regimen desired for the composition.

In addition to the subject compound, the compositions of the subjectinvention contain a pharmaceutically-acceptable carrier. The term“pharmaceutically-acceptable carrier”, as used herein, means one or morecompatible solid or liquid filler diluents or encapsulating substanceswhich are suitable for administration to an animal, preferably a mammal,more preferably a human. The term “compatible”, as used herein, meansthat the components of the composition are capable of being commingledwith the subject compound, and with each other, in a manner such thatthere is no interaction which would substantially reduce thepharmaceutical efficacy of the composition under ordinary usesituations. Pharmaceutically-acceptable carriers must, of course, be ofsufficiently high purity and sufficiently low toxicity to reader themsuitable for administration to the animal, preferably a mammal, morepreferably a human being treated.

Some examples of substances which can serve aspharmaceutically-acceptable carriers or components thereof are sugars,such as lactose, glucose and sucrose; starches, such as corn starch andpotato starch; cellulose and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powderedtragacanth; malt; gelatin; talc; solid lubricants, such as stearic acidand magnesium stearate; calcium sulfate; vegetable oils, such as peanutoil, cottonseed oil, sesame oil, olive oil, corn oil and oil oftheobroma; polyols such as propylene glycol, glycerine, sorbitol,mannitol, and polyethylene glycol; alginic acid; emulsifiers, such asthe Tweens”; wetting agents, such sodium lauryl sulfate; coloringagents; flavoring agents; tableting agents, stabilizers; antioxidants;preservatives; pyrogen-free water; isotonic saline; and phosphate buffersolutions.

The choice of a pharmaceutically-acceptable carrier to be used inconjunction with the subject compound is basically determined by the waythe compound is to be administered.

If the subject compound is to be injected, the preferredpharmaceutically-acceptable carrier is sterile, physiological saline,with blood-compatible suspending agent, the pH of which has beenadjusted to about 7.4.

In particular, pharmaceutically-acceptable carriers for systemicadministration include sugars, starches, cellulose and its derivatives,malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils,polyols, alginic acid, phosphate buffer solutions, emulsifiers, isotonicsaline, and pyrogen-free water. Preferred carriers for parenteraladministration include propylene glycol, ethyl oleate, pyrrolidone,ethanol, and sesame oil. Preferably, the pharmaceutically-acceptablecarrier, in compositions for parenteral administration, comprises atleast about 90% by weight of the total composition.

The compositions of this invention are preferably provided in unitdosage form. As used herein, a “unit dosage form” is a composition ofthis invention containing an amount of a Formula (I) compound that issuitable for administration to an animal, preferably a mammal, morepreferably a human subject, in a single dose, according to good medicalpractice. These compositions preferably contain from about 5 mg(milligrams) to about 1000 mg, more preferably from about 10 mg to about500 mg, more preferably from about 10 mg to about 300 mg, of a Formula(I) compound.

The compositions of this invention may be in any of a variety of forms,suitable (for example) for oral, rectal, topical, nasal, ocular orparenteral administration. Depending upon the particular route ofadministration desired, a variety of pharmaceutically-acceptablecarriers well-known in the art may be used. These include solid orliquid fillers, diluents, hydrotropes, surface-active agents, andencapsulating substances. Optional pharmaceutically-active materials maybe included, which do not substantially interfere with the inhibitoryactivity of the Formula (I) compound. The amount of carrier employed inconjunction with the Formula (I) compound is sufficient to provide apractical quantity of material for administration per unit dose of theFormula (I) compound. Techniques and compositions for making dosageforms useful in the methods of this invention are described in thefollowing references, all incorporated by reference herein: ModernPharmaceutics, Chapters 9 and 10 (Banker & Rhodes, editors, 1979);Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); andAnsel, Introduction to Pharmaceutical Dosage Forms 2d Edition (1976).

In addition to the subject compound, the compositions of the subjectinvention contain a pharmaceutically-acceptable carrier. The term“pharmaceutically-acceptable carrier”, as used herein, means one or morecompatible solid or liquid filler diluents or encapsulating substanceswhich are suitable for administration to an animal preferably a mammalmore preferably a human. The term “compatible”, as used herein, meansthat the components of the composition are capable of being commingledwith the subject compound, and sit each other, in a manner such thatthere is no interaction which would substantially reduce thepharmaceutical efficacy of the composition under ordinary usesituations. Pharmaceutically-acceptable carriers must, of course, be ofsufficiently high purity and sufficiently low toxicity to render themsuitable for administration to the animal, preferably a mammal morepreferably a human being treated.

Some examples of substances which can serve aspharmaceutically-acceptable carriers or components thereof are sugars,such as lactose, glucose and sucrose; starches, such as corn starch andpotato starch; cellulose and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powderedtragacanth; malt; gelatin; talc; solid lubricants, such as stearic acidand magnesium stearate; calcium sulfate; vegetable oils, such as peanutoil, cottonseed oil, sesame oil, olive oil, corn oil, and oil oftheobroma; polyols such as propylene glycol, glycerine, sorbitolmannitol, and polyethylene glycol; alginic acid; emulsifiers, such asthe Tweens”; wetting agents, such sodium lauryl sulfate; coloringagents; flavoring agents; tableting agents, stabilizers; antioxidants;preservatives; pyrogen-free water; isotonic saline; and phosphate buffersolutions.

The choice of a pharmaceutically-acceptable carrier to be used inconjunction with the subject compound is basically determined by the waythe compound is to be administered.

If the subject compound is to be injected, the preferredpharmaceutically-acceptable carrier is sterile, physiological saline,with blood-compatible suspending agent, the pH of which has beenadjusted to about 7.4.

Various oral dosage forms can be used, including such solid forms astablets, capsules, granules and bulk powders. These oral forms comprisea safe and effective amount, usually at least about 5%, and preferablyfrom about 25% to about 50%, of the Formula (I) compound. Tablets can becompressed, tablet triturates, enteric-coated, sugar-coated,film-coated, or multiple-compressed, containing suitable binders,lubricants, diluents, disintegrating agents, coloring agents, flavoringagents, flow-inducing agents, and melting agents. Liquid oral-dosageforms include aqueous solutions, emulsions, suspensions, solutionsand/or suspensions reconstituted from non-effervescent granules, andeffervescent preparations reconstituted from effervescent granules,containing suitable solvents, preservatives, emulsifying agents,suspending agents, diluents, sweeteners, melting agents, coloring agentsand flavoring agents.

The pharmaceutically-acceptable carrier suitable for the preparation ofunit dosage forms for peroral administration are well-known in the art.Tablets typically comprise conventional pharmaceutically-compatibleadjuvants as inert diluents, such as calcium carbonate, sodiumcarbonate, mannitol, lactose and cellulose; binders such as starch,gelatin and sucrose; disintegrants such as starch, alginic acid andcroscarmelose; lubricants such as magnesium stearate, stearic acid andtalc. Glidants such as silicon dioxide can be used to improve flowcharacteristics of the powder mixture. Coloring agents, such as the FD&Cdyes, can be added for appearance. Sweeteners and flavoring agents, suchas aspartame, saccharin, menthol peppermint, and fruit flavors, areuseful adjuvants for chewable tablets. Capsules typically comprise oneor more solid diluents disclosed above. The selection of carriercomponents depends on secondary considerations like taste, cost, andshelf stability, which are not critical for the purposes of the subjectinvention, and can be readily made by a person skilled in the art.

Peroral compositions also include liquid solutions, emulsions,suspensions, and the like. The pharmaceutically-acceptable carrierssuitable for preparation of such compositions are well known in the art.Typical components of carriers for syrups, elixirs, emulsions andsuspensions include ethanol, glycerol, propylene glycol, polyethyleneglycol, liquid sucrose, sorbitol and water. For a suspension, typicalsuspending agents include methyl cellulose, sodium carboxymethylcellulose, Avicel” RC-591, tragacanth and sodium alginate; typicalwetting agents include lecithin and polysorbate 80; and typicalpreservatives include methyl paraben and sodium benzoate. Peroral liquidcompositions may also contain one or more components such as sweeteners,flavoring agents and colorants disclosed above.

Such compositions may also be coated by conventional methods, typicallywith pH or time dependent coatings, such that the subject compound isreleased in the gastrointestinal tract in the vicinity of the desiredtopical application, or at various times to extend the desired action.Such dosage forms typically include, but are not limited to, one or moreof cellulose acetate phthalate, polyvinylacetate phthalate,hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragit”coatings, waxes and shellac.

Compositions of the subject invention may optionally include other drugactives.

Other compositions useful for attaining systemic delivery of the subjectcompounds include sublingual, buccal and nasal dosage forms. Suchcompositions typically comprise one or more of soluble filler substancessuch as sucrose, sorbitol and mannitol; and binds such as acacia,microcrystalline cellulose, carboxymethyl cellulose and hydroxypropylmethyl cellulose. Glib lubricants, sweeteners, colorants, antioxidantsand flavoring agent disclosed above may also be included.

The compositions of this invention can also be administered topically toa subject, e.g., by the direct laying on or spreading of the compositionon the epidermal or epithelial tissue of the subject, or transdermallyvia a “patch”. Such compositions include, for example, lotions, creams,solutions, gels and solids. These topical compositions preferablycomprise a safe and effective amount, usually at least about 0.1%, andpreferably from about 1% to about 5%, of the Formula (I) compound.Suitable carriers for topical administration preferably remain in placeon the skin as a continuous film, and resist being removed byperspiration or immersion in water. Generally, the carrier is organic innature and capable of having dispersed or dissolved therein the Formula(I) compound. The carrier may include pharmaceutically to acceptableemolients, emulsifiers, thickening agents, solvents and the like.

Methods of Administration:

This invention also provides methods of treating or preventing disordersassociated with excess or undesired metalloprotease activity in a humanor other animal subject, by administering a safe and effective amount ofa Formula (I) compound to said subject. As used herein, a “disorderassociated with excess or undesired metalloprotease activity” is anydisorder characterized by degradation of matrix proteins. The methods ofthe invention are useful in treating disorders described above.

The Formula (I) compounds and compositions of this invention can beadministered topically or systemically. Systemic application includesany method of introducing Formula (I) compound into the tissues of thebody, e.g., intra-articular (especially in treatment of rheumatoidarthritis), intrathecal, epidural, intramuscular, transdermal,intravenous, intraperitoneal, subcutaneous, sublingual, rectal, and oraladministration. The Formula (I) compounds of the present invention arepreferably administered orally.

The specific dosage of inhibitor to be administered, as well as theduration of treatment, and whether the treatment is topical or systemicare interdependent. The dosage and treatment regimen will also dependupon such factors as the specific Formula (I) compound used, thetreatment indication, the ability of the Formula (I) compound to reachminimum inhibitory concentrations at the site of the metalloprotease tobe inhibited, the personal attributes of the subject (such as weight),compliance with the treatment regimen, and the presence and severity ofany side effects of the treatment.

Typically, for a human adult (weighing approximately 70 kilograms), fromabout 5 mg to about 3000 mg, more preferably from about 5 mg to about1000 mg, more preferably from about 10 mg to about 100 mg, of Formula(I) compound are administered per day for systemic administration. It isunderstood that these dosage ranges are by way of example only, and thatdaily administration can be adjusted depending on the factor listedabove.

A preferred method of administration for treatment of rheumatoidarthritis is oral or parenterally via intra-articular injection. As isknown and practiced in the art, all formulations for parenteraladministration must be sterile. For mammals, especially humans,(assuming an approximate body weight of 70 kilograms) individual dosesof from about 10 mg to about 1000 mg are preferred.

A preferred method of systemic administration is oral. Individual dosesof from about 10 mg to about 1000 mg, preferably from about 10 mg toabout 300 mg are preferred.

Topical administration can be used to deliver the Formula (I) compoundsystemically, or to treat a subject locally. The amounts of Formula (I)compound to be topically administered depends upon such factors as skinsensitivity, type and location of the tissue to be treated, thecomposition and carrier (if any) to be administered, the particularFormula (I) compound to be administered, as well as the particulardisorder to be treated and the extent to which systemic (asdistinguished from local) effects are desired.

The inhibitors of the invention can be targeted to specific locationswhere the metalloprotease is accumulated by using targeting ligands. Forexample, to focus the inhibitors to metalloprotease contained in atumor, the inhibitor is conjugated to an antibody or fragment thereofwhich is immunoreactive with a tumor marker as is generally understoodin the preparation of immunotoxins in general. The targeting ligand canalso be a ligand suitable for a receptor which is present on the tumor.Any targeting ligand which specifically reacts with a marker for theintended target tissue can be used. Methods for coupling the inventioncompound to the targeting ligand are well known and are similar to thosedescribed below for coupling to carrier. The conjugates are formulatedand administered as described above.

For localized conditions, topical administration is preferred. Forexample, to treat ulcerated cornea, direct application to the affectedeye may employ a formulation as eyedrops or aerosol. For cornealtreatment, the compounds of the invention can also be formulated asgels, drops or ointments, or can be incorporated into collagen or ahydrophilic polymer shield. The materials can also be inserted as acontact lens or reservoir or as a subconjunctival formulation. Fortreatment of skin inflammation, the compound is applied locally andtopically, in a gel, paste, salve or ointment. The mode of treatmentthus reflects the nature of the condition and suitable formulations forany selected route are available in the art.

In all of the foregoing, of course, the compounds of the invention canbe administered alone or as mixtures, and the compositions may furtherinclude additional drugs or excipients as appropriate for theindication.

Some of the compounds of the invention also inhibit bacterialmetalloproteases. Some bacterial metalloproteases may be less dependenton the stereochemistry of the inhibitor, whereas substantial differencesare found between diastereomers in their ability to inactivate themammalian proteases. Thus, this pattern of activity can be used todistinguish between the mammalian and bacterial enzymes.

Preparation and Use of Antibodies:

The invention compounds can also be utilized in immunization protocolsto obtain antisera immunospecific for the invention compounds. As theinvention compounds are relatively small, they are advantageouslycoupled to antigenically neutral carriers such as the conventionallyused keyhole limpet hemocyanin (KLH) or serum albumin carriers. Forthose invention compounds having a carboxyl functionality, coupling tocarrier can be done by methods generally known in the art. For example,the carboxyl residue can be reduced to an aldehyde and coupled tocarrier through reaction with sidechain amino groups in protein-basedcarriers, optionally followed by reduction of imino linkage formed. Thecarboxyl residue can also be reacted with sidechain amino groups usingcondensing agents such as dicyclohexyl carbodiimide or othercarbodiimide dehydrating agents.

Linker compounds can also be used to effect the coupling; bothhomobifunctional and heterobifunctional linkers are available fromPierce Chemical Company, Rockford, Ill. The resulting immunogeniccomplex can then be injected into suitable mammalian subjects such asmice, rabbits, and the like. Suitable protocols involve repeatedinjection of the immunogen in the presence of adjuvants according to aschedule which boosts production of antibodies in the serum. The titersof the immune serum can readily be measured using immunoassayprocedures, now standard in the art, employing the invention compoundsas antigens.

The antisera obtained can be used directly or monoclonal antibodies maybe obtained by harvesting the peripheral blood lymphocytes or the spleenof the immunized animal and immortalizing the antibody-producing cells,followed by identifying the suitable antibody producers using standardimmunoassay techniques.

The polyclonal or monoclonal preparations are then useful in monitoringtherapy or prophylaxis regimens involving the compounds of theinvention. Suitable samples such as those derived from blood, senturine, or saliva can be tested for the presence of the administeredinhibitor at various times during the treatment protocol using standardimmunoassay techniques which employ the antibody preparations of theinvention.

The invention compounds can also be coupled to labels such asscintigraphic labels, e.g., technetium 99 or I-131, using standardcoupling methods. The labeled compounds are administered to subjects todetermine the locations of excess amounts of one or moremetalloproteases in vivo. The ability of the inhibitors to selectivelybind metalloprotease is thus taken advantage of to map the distributionof these enzymes in situ. The techniques can also be employed inhistological procedures and the labeled invention compounds can be usedin competitive immunoassays.

The following non-limiting examples illustrate the compounds,compositions, and uses of the present invention.

EXAMPLES

Compounds are analyzed using ¹H and ¹³C NMR, Elemental analysis, massspectra and/or IR spectra, as appropriate.

Typically tetrahydrofuran (THF) is distilled from sodium andbenzophenone, diisopropylamine is distilled from calcium hydride and allother solvents are purchased as the appropriate grade. Chromatography isperformed on silica gel (70-230 mesh; Aldrich) or (230-400 mesh; Merk)as appropriate. Thin layer chromatography analysis (TLC) is performed onglass mounted silica gel plates (200-300 mesh; Baker) and visualizedwith UV or 5% phosphomolybdic acid in EtOH.

Examples 1-25

The following chart shows the structure of compounds made according tothe description in Examples 1-19 described below:

Example *(configuration) Y Z 1 d a-OH H 2 d b-OH H 3 l a-OH H 4 l b-OH H5 d b-OMe H 6 d b-(2-benzathiazole) H 7 d a-(2-benzathiazole) H 8 db-2(3N-methyl-imidazole) H 9 d a-2(3N-methyl-lmidazole) H 10 d b-OPh H11 d b-O(C₆H₄)OCH₂Ph H 12 d b-O(2-(C₆H₄)NHPh) H 13 d b-O(3-Pyridyl) H 14d b-SPh H 15 d b-S(4-C₆H₄OMe) H 16 d b-S(3-C₆H₄OMe) H 17 d a-OCH₂OCH₂CH₃H 18 d a-OCH₂OCH₂Ph H 19 d a-OCH₂OCH₂CH₃OCH₃ H 20 d b-SH H 21 racemic Hphenyl 22 d a-OH, b-Et H 23 d a-OH, b-Ph H 24 d b-O(4-C₆H₄-Octyl) H 25 da-OH gem-(CH₃)₂Ph-phenylMe=methylC₆H₄-phenyl diradical

Example 1

a.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-4R-hydroxy-pyrrolidine:cis-Hydroxy-D-proline (50 g, 0.38 mole) is dissolved in water:dioxane(1:1, 300 mL) with triethylamine (135 mL, 0.96 mole).4-Methoxyphenylsulfonyl chloride (87 g, 0.42 mole) is added along with2,6-dimethylaminopyridine (4.6 g, 0.038 mole) and the mixture is stirred14 hr. at room temperature. The mixture is then concentrated and dilutedwith EtOAc. Layers are separated and the organic layer is washed 2× with1N HCl, 1× with brine, dried over MgSO₄, filtered and evaparated to give83 g of solid material which is dissolved in MeOH (500 mL). Thionylchloride (50 mL) is added dropwise and the resulting mixture stirred for14 hr. The mixture is then evaparated to dryness and triturated withCHCl₃ to give a white solid which is sufficiently pure to carry forwardwithout purification. CI⁺ MS: m/z (rel intensity) 316 (M⁺+H, 100), 256(30), 146 (45).

b.(1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-hydroxypyrrolidine:

The starting methylester 1a (361 mg, 1.15 mmole) is taken in 1 mL ofmethanol, treated with NH₂OK (1.45 mL, 0.86 M in methanol, solutionprepared as described in Fieser and Fieser, Vol 1, p 478) and stirredovernight. The following morning the material is concentrated andpartitioned between EtOAc and 1N HCl. The organic layer is washed withbrine, dried over MgSO₄, filtered and evaparated to give crude materialwhich is recrystallized from hex:EtOAc at −4° C. to give the desiredwhite solid and recovered oil. ESI MS: m/z (rel intensity) 317 (M+H⁺,100), 334 (M+NH₄ ⁺, 20), 339 (M+Na⁺, 35).

Example 2

a.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-benzoyloxypyrrolidine:The alcohol 1a (780 mg, 2.48 mmole) is dissolved in 5 mL of methylenechloride. Benzoic acid (604 mg, 4.95 mmole) and triphenyl phosphine (779mg, 2.98 mmole) are then added, followed by diethyl azodicarboxylate(429 mL, 2.73 mmole). After 3 hrs, the reaction mixture is filtered andsilica gel is added to the filtrate to adsorb the solutes and themixture is concentrated to dryness. The resulting solid mixture ispoured onto the top of a flash silica column which is eluted withhex:EtOAc (1:1 to 0:1) to give the desired product as a white solid. CI⁺MS: m/z (rel intensity) 420.0 (M⁺+H, 100), 250.1 (95), 126.0 (45).

b.(1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-hydroxypyrrolidine:The methyl-benzyl diester 2a (175 g, 0.418 mmole) is taken in 2.5 mL ofmethanol, treated with NH₂OK (0.48 mL, 0.86 M in methanol, solutionprepared as described in Fieser and Fieser, Vol 1, p 478) and stirredovernight. The following morning, dry silica (1 mL) is added to themixture and the solvent removed under vaccuum. The dry silica is pouredon the top of a flash silica gel column which is subsequently elutedwith EtOAc:MeOH:HCO₂H (90:9:1) to give a white solid which is thenrecrystallized from hexane:EtOAc (1:5) to give white crystals. ESI MS:m/z (rel intensity) 317.1 (M⁺+H, 100), 339.1 (M⁺+Na, 20).

Example 3

a.(1N)-4-Methoxyphenylsulfonyl-(2S)-carbomethoxy-(4R)-hydroxypyrrolidine:To a solution of trans-4-hydroxy-L-proline methyl ester (2.0 g, 11.0mmol) in 10 mL DMF is added 2 mL N-methylmorpholine and4-methoxybenzenesulfonyl chloride and is stirred for 1 hr. The solutionis then partitioned between EtOAc and water, washed with 1 N HCl,NaHCO₃, NaCl, and dried over MgSO₄. The crude product is thenchromatographed over silica with EtOAc to give the title compound. CI⁺MS: m/z (rel intensity) 316 (100, M⁺+H).

b.(1N)-4-Methoxyphenylsulfonyl-(2S)-N-hydroxycarboxamido-(4R)-hydroxypyrrolidine:The starting ester 3a (500 mg, 1.6 mmol) is added to NH₂OK (1.9 mL, 1 eqin MeOH, prepared according to Fieser and Fieser, Vol 1, p 478) andstirred for 15 hr. The solvent is evaporated and the residue isdissolved in 1N HCl and extracted with EtOAc. The organic layer is driedover MgSO₄, evaporated and the residue is recrystallized fromEtOAc:Hexanes to give the title compound. ESI MS: m/z (rel intensity)317 (100, M⁺+H), 256 (70).

Example 4

a.(1N)-4-Methoxyphenylsulfonyl-(2S)-carbomethoxy-(4S)-hydroxy-pyrrolidine:To a solution of cis-4-hydroxy-L-proline methyl ester (2.0 g, 1.0 mmol)in 10 mL DMF is added 2 mL N-methylmorpholine and4-methoxybenzenesulfonyl chloride and is sired for 1 hr. The solution isthen partitioned between EtOAc and water, washed with 1 N HCl, NaHCO₃,NaCl, and dried over MgSO₄. The crude product is then chromatographedover silica with EtOAc to give the title compound. CI⁺ MS: m/z (relintensity) 316 (100, M⁺+H).

b.(1N)-4-Methoxyphenylsulfonyl-(2S)-N-hydroxycarboxamido-(4S)-hydroxy-pyrrolidine:The starting ester 4a (500 mg, 1.6 mmol) is added to NH₂OK (1.9 mL, 1 eqin MeOH, prepared according to Fieser and Fieser, Vol 1, p 478) andstirred for 15 hr. The solvent is evaporated and the residue isdissolved in 1N Ha and extracted with EtOAc. The organic layer is driedover MgSO₄, evaporated and the residue is recrystallized fromEtOAc:Hexanes to give the title compound. ESI MS: m/z (rel intensity)317 (100, M⁺+H), 256 (70).

Example 5

a. (1N)-4-Methoxyphenylsulfonyl-(2R)-carboxy-(4S)-hydroxy-pyrrolidine:The diester 2a (10 g, 24 mmole) is dissolved in water:dioxane (1:10, 50mL) and stirred overnight in the presence of lithium hydroxidemonohydrate (5 g, 120 mmole). The mixture is acidified with 1N HCl andextracted with EtOAc, washed with brine, dried over MgSO₄, filtered andevaparated to give solid material which is recrystallized fromEtoAc:hexanes to give the title compound as a white solid. ESI MS: m/z(rel intensity) 302 (M⁺+H, 100), 318 (M⁺+NH₃, 30).

b.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-methoxy-pyrrolidine:The carboxylic acid 5a (4.0 g, 13.2 mmol) is stirred in THF at roomtemperature and then sodium hydride (1.58 g, 39.6 mmol 3 equiv, 60% inoil) is slowly added. After hydrogen gas evolution had ceased, methyliodide (5.52 g, 39.6 mmol, 3 equiv) is added to the reaction mixture.The resulting solution is stirred at room temperature for 1 hour. Thereaction mixture is quenched by the addition of water and then extractedwith EtOAc. The organic extracts are concentrated to an oil and thenmethanol and 3 drops of conc. HCl are added. The solution is then heatedto reflux for 24 hours. The solvent is removed and the product ispurified by silica gel chromatography (1/1 hexane/EtOAc followed by 100%EtOAc) to afford the desired methyl ester as a white crystalline solid.CI⁺ MS: m/z (rel intensity) 330 (M⁺, 100).

c.(1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-methoxypyrrolidine:

The ester 5b (0.50 g, 1.52 mmol) is taken in 2 mL of methanol, treatedwith NH₂OK (2.5 mL, 0.86 M in methanol, solution prepared as describedin Fieser and Fieser, Vol 1, p 478) and stirred overnight. The solutionis poured into water and acidified to pH˜2. The resulting solution isextracted with CH₂Cl₂, dried (Na₂SO₄) and concentrated to a white solid.Purification of the resulting solid is accomplished by recrystallizationfrom EtOAc:hexane (3:1) to afford the desired product as a whitecrystalline solid. ESI MS: m/z (rel intensity) 331.0 (M+H⁺, 100), 348.0(M+NH₄ ⁺, 85), 353.0 (M+Na⁺, 45).

Example 6

a.(1N)-4-Methoxyphenylsulfonamido-(2R)-carbomethoxy-(4R)-trifluoromethanesulfonyl-pyrrolidine:The starting alcohol 1a (221 mg, 0.702 mmole) is taken in dry CH₂Cl₂under argon and cooled to 0° C. 2,6-Lutidine (326 mL, 2.81 mmole) isadded via syringe followed by slow syringe addition oftrifluoromethanesulfonyl anhydride (153 mL, 0.912 mmole) and theresulting yellow mixture is 1 hr at 0° C. and then partitioned betweenwater and EtOAc. The organic layer is dried over MgSO₄, filtered andevaporated. The crude residue is chromatographed over flash silica withhexane:EtOAc (4:1 to 1:1) to give the desired off-white solid. CI⁺ MS:m/z (rel intensity) 411 (M+NH₄ ⁺, 25) 394 (M⁺+H, 21), 224 (82), 155(23), 128 (100).

b.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-(2-mercapto-benzothiazolyl)-pyrrolidine:The triflate 6a (145 mg, 0.353 mmole) is dissolved in methylene chloride(1 mL) under argon and 2,6-lutidine (61 mL, 0.529 mmole) is added viasyringe followed by 2-mercapto-benzothiazole (65 mg, 0.388 mmole). After1 hr., silica gel (1.5 mL) is added to the mixture which is thenevaparated to dryness. The resulting solid mixture is then added to thetop of a flash silica column which is then eluted with hexane:EtOAc (1:1to 1:5) to give the pure title compound as a clear oil. CI⁺ MS: m/z (relintensity) 465 (M⁺+H, 10), to 300 (38), 240 (13), 168 (21), 150 (33),136 (100).

c.(1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-2-mercapto-benzothiazolyl)-pyrrolidine:

A 1.76M solution of potassium hydroxylamine in methanol is prepared. The1.76M solution (0.4 mL, 0.711 mmoles) is added directly to the methylester 6b (0.165 g, 0.356 mmoles) and the reaction mixture stirredovernight. The solution is acidified with 1N HCl, then extracted 3 timeswith ethyl acetate, dried with magnesium sulfate, filtered andevaporated. Chromatography is performed on silica gel using ethylacetate:hexane:formic acid (1:1:0.1) to give the title compound. ESI MS:m/z (rel intensity) 466.0 (M⁺+H, 100), 408.2 (M⁺+Na, 20).

Example 7

a.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-hydroxy-pyrrolidine:The acid 5a (4 g, 9.55 mmole) is dissolved in methanol (50 mL), treatedwith thionyl chloride (3 mL) and stirred overnight. The mixture is thenevaparated to dryness and recrystallized from EtOAc:hexanes to give thetitle compound as a white solid. CI⁺ MS: m/z (rel intensity) 316 (M⁺+H,100), 256 (60), 158 (25), 146 (30).

b.(1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4R)-(2-mercapto-benzothiazolyl)-pyrrolidine:The starting alcohol 7a (323 mg, 1.03 mmole) is taken in 4 mL of CH₂Cl₂and to this mixture is added triphenylphosphene (351 mg, 1.35 mmole),2-mercaptobenzothiazole (189 mg, 1.13 mg), anddiethyl-diazadicarboxylate (195 mM, 1.24 mmole) and the mixture isstirred for 0.5 hr. at which time 5 mL of silica gel is added to themixture which is then concentrated to dryness. The dry residue is pouredonto the top of a flash silica column and eluted with hexane:EtOAc (4:1to 1:4) to give a clear oil. CI⁺ MS: m/z (rel intensity) 465 (M⁺+H, 5),300 (20), 150 (25), 136 (100), 128 (25).

c.(1N)-4-Methoxyphenylsulfonyl-(4R)-N-hydroxycarboxamido-(4R)-(2-mercaptobenzo-thiazolyl)-pyrrolidine:The methyl ester 7b (372 g, 0.802 mmole) is taken in 1.5 mL of methanol,treated with NH₂OK (1.4 ml, 0.86 M in methanol, solution prepared asdescribed in Fieser and Fieser, Vol 1, p 478) and stirred overnight. Thefollowing morning, dry silica (1.5 mL) is added to the mixture and thesolvent removed under vaccuum. The dry silica is poured on the top of aflash silica gel column which is subsequently eluted with hexane:EtOAc(1:2) to remove impurities and then EtOAC:MEOH (9:1). The resultingproduct is recrystallized from chloroform to give white crystals. ESIMS: m/z (rel intensity) 466.1 (M⁺+H, 100), 488.0 (M⁺+Na, 12).

Example 8

a.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-[(1N)-methyl-2-mercaptoimidazyl]-pyrrolidine:The alcohol 1a (700 mg, 2.22 mmole) is dissolved in 12 mL of methylenechloride. 2-Mercapto-1-methylimidazole (304 mg, 2.66 mmole) andtriphenyl phosphine (873 mg, 3.33 mmole) are then added, followed bydiethyl azodicarboxylate (420 to mL, 2.66 mmole). After 3 hrs, thereaction mixture is filtered and silica gel is added to the filtrate toadsorb the solutes and the mixture is concentrated to dryness. Theresulting solid mixture is poured onto the top of a flash silica columnwhich is eluted with hex:EtOAc (1:1 to 0:1) to give the desired productas a white solid. CI⁺ MS: m/z (rel intensity) 412 (M⁺+H, 100), 242 (5),115 (28).

b.(1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-[(1N)-methyl-2-mercaptoimidazyl]-pyrrolidine:The ester 8a (500 mg, 1.22 mmole) is taken in 1 mL of methanol treatedwith NH₂OK (2.11 ml, 0.86 M in methanol, solution prepared as describedin Fieser and Fieser, Vol 1, p 478) and stirred overnight. The followingmorning, dry silica (2 mL) is added to the mixture and the solventremoved under vaccuum. The dry silica is poured on the top of a flashsilica gel column which is subsequently eluted with hexane:EtOAc (1:1 to0:1) followed by EtOAc:MeOH:NH₄OH (9:1:0.1) to give a white solid. ESIMS: m/z (rel intensity) 413 (M⁺+H, 100), 435 (M⁺+Na, 20).

Example 9

a.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4R)-[(1N)-methyl-2-mercaptoimidazyl]-pyrrolidine:The alcohol 7a (700 mg, 2.22 mmole) is dissolved in 12 mL of methylenechloride. 2-Mercapto-1-methylimidazole (304 mg, 2.66 mmole) andtriphenyl phosphine (873 mg, 3.33 mmole) are then added, followed bydiethyl azodicarboxylate (420 mL, 2.66 mmole). After 3 hrs, the reactionmixture is filtered and silica gel is added to the filtrate to adsorbthe solutes and the mixture is concentrated to dryness. The resultingsolid mixture is poured onto the top of a flash silica column which iseluted with hex:EtOAc (1:1 to 0:1) to give the desired product as awhite solid CI⁺ MS: m/z (rel intensity) 412 (M⁺+H, 100), 242 (5), 115(28).

b.(1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4R)-[(1N)-methyl-2-mercaptoimidazyl]-pyrrolidine:The ester 9a (500 mg, 122 mmol) is taken in 5 mL of methanol, treatedwith NH₂OK (2.11 mL, 0.86 M in methanol, solution prepared as describedin Fieser and Fieser, Vol 1, p 478) and stirred overnight. The followingmorning, dry silica (2 mL) is added to the mixture and the solventremoved under vaccuum. The dry silica is poured on the top of a flashsilica gel column which is subsequently eluted with hexane:EtOAc (1:1 to0:1) to give a white solid. ESI MS: m/z (rel intensity) 413.0 (M⁺+H,100), 435.0 (M⁺+Na, 20).

Example 10

a.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-phenoxy-pyrrolidine:The alcohol 1a (1.3 g, 4.12 mmole) is dissolved in 3 mL of methylenechloride. Phenol (0.8 g, 8.24 mmole) and triphenyl phosphine (2.16 g,8.24 mmole) are then added, followed by diethyl azodicarboxylate (1.2mL, 7.84 mmole). After 3 hrs, the reaction mixture is filtered andconcentrated to an oil, which is purified on silica gel using ethylacetate:hexane:methylene chloride (1:3:1) to give the desired product asan oil. CI⁺ MS: m/z (rel intensity) 409 (100, M⁺+NH₃), 392 (72, M⁺+H).

b.(1N)-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-phenoxypyrrolidine:

The methyl ester 10a (0.6 g, 1.53 mmole) is taken in 3 mL of methanol,treated with NH₂OK (5 mL, 1.7 M in methanol, solution prepared asdescribed in Fieser and Fieser, Vol 1, p 478) and stirred overnight. Thefollowing morning, dry silica (1.5 mL) is added to the mixture and thesolvent removed under vaccuum. The dry silica is poured on the top of aflash silica gel column which is subsequently eluted with formicacid:EtOAc (0:1 to 3:97) to give 0.36 g of white foamy solid, which isrecrystallized from hexane:EtOAc to give the desired product ESI MS: m/z(rel intensity) 415 (38, M⁺+Na), 410 (10, M⁺+NH₄), 393 (100, M⁺+H).

Example 11

a.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-[(4-benzyloxy)-phenoxy]-pyrrolidine:Triphenylphosphine (2.5 g, 9.51 mmole) is dissolved in 20 mL of THF.Diethyl azodicarboxylate (1.9 mL, 9.51 mmole) is added dropwise at 0° C.After 30 min with stirring, a solution of 4-(benzyloxy)phenol (2.38 g,11.9 mmole) and the alcohol 1a (1.5 g, 4.76 mmole) in 15 mL of THF isadded dropwise. The reaction is stirred at 0° C. for 30 min, roomtemperature overnight and concentrated to an oil. The crude product ispurified by flash chromatography (hexane/EtOAc, 4:1 to 1:1) on silicagel to give the desired product. CI⁺ MS: m/z (rel intensity) 498 (100,M⁺+H), 328 (24).

b.(1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-(4-benzyloxy)-phenoxypyrrolidine:The methyl ester 11a (0.7, 1.4 mmole) is taken in 1 mL of methanol,treated with NH₂OK (8 ml, 1.7 M in methanol, solution prepared asdescribed in Fieser and Fieser, Vol 1, p 478) and stirred for 3 hr.Silica (1.5 mL) is added to the mixture and the solvent is removed undervaccuum. The dry silica is poured on the top of a flash silica gelcolumn which is subsequently eluted with hexane:EtOAc (1:1) toEtOAc:CH₃OH (1:0 to 1:1) to give the desired product as white foamysolid. ESI MS: m/z (rel intensity) 521 (30, M⁺+Na), 516 (14, M⁺+NH₄),499(100, M⁺+H).

Example 12

a.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-(3-N-phenyl-amino)-phenoxylpyrrolidine:Triphenylphosphine (2.5 g, 9.52 mmole) is dissolved in 20 mL of THF.Diethyl azodicarboxylate (1.95 mL, 9.52 mmole) is added dropwise at 0°C. After 30 min with stirring, a solution of 3-hydroxydiphenylamine (2.2g, 11.9 mmole) and the alcohol 1a (1.5 g, 4.76 mmole) in 15 mL of THF isadded dropwise. The reaction is stirred at 0° C. for 30 min., roomtemperature for 2 hr and concentrated to an oil. The crude product ispurified by flash chromatography (hexane/EtOAc, 7:3 to 1:1) on silicagel to give the desired product ESI MS: m/z (rel intensity) 505 (8,M⁺+Na), 483 (100, M⁺+H).

b.(1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-(3-N-phenylamino)-phenoxylpyrrolidine:The methyl ester 12a (0.68 g, 1.38 mmole) is taken in 2 mL of methanol,treated with NH₂OK (6 ml, 1.7 M in methanol, solution prepared asdescribed in Fieser and Fieser, Vol 1, p 478) and stirred overnight. Thefollowing morning, dry silica (1.5 mL) is added to the mixture and thesolvent is removed under vaccuum. The dry silica is poured on the top ofa flash silica gel column which is subsequently eluted with EtOAc:CH₃OH(1:0 to 9:1) to give the desired product as a white foamy solid. ESI MS:m/z (rel intensity) 506 (36, M⁺+Na), 484 (100, M⁺+H).

Example 13

a.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-(3-pyridinoxy)-pyrrolidine:Triphenylphosphine (2.42 g, 9.2 mmole) is dissolved in 20 mL of THF.Diethyl azodicarboxylate (1.81 mL, 9.2 mmole) is added dropwise at 0° C.After 30 min with stirring, a solution of 3-hydroxypyridine (1.32 g,13.83 mmole) and the alcohol 1a (1.5 g, 4.61 mmole) in 15 mL of THF isadded dropwise. The reaction is stirred at 0° C. for 30 min, roomtemperature for 2 hr and concentrated to an oil. The crude product ispurified by flash chromatography (hexane/EtOAc: 1/1 to EtOAc) on silicagel to give the desired product. CI⁺ MS: m/z (rel intensity) 393 (100,M⁺+H), 279 (88), 223 (70).

b.(1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-phenoxypyrrolidine:The methyl ester 13a (0.18 g, 0.46 mmole) is taken in 1 mL of methanol,treated with NH₂OK (0.5 ml, 1.7 M in methanol, solution prepared asdescribed in Fieser and Fieser, Vol 1, p 478) and stirred overnight. Thefollowing morning, dry silica (1.5 mL) is added to the mixture and thesolvent is removed under vaccuum. The dry silica is poured on the top ofa flash silica gel column which is subsequently eluted with EtOAc:CH₃OH(1:0 to 1:1) to give a white foamy solid which is crystallized frommethylene chloride to give the desired product as a white solid. ESI MS:m/z (rel intensity) 432 (10, M⁺+K), 416 (8, M⁺+Na), 394 (100, M⁺+H).

Example 14

a.(1N)-4-Methoxyphenylsulfonyl(2R)-carbomethoxy-(4S)-mercaptophenylpyrrolidine:The alcohol 1a (200 mg, 0.634 mmole) is dissolved in 2 mL of methylenechloride. Thiophenol (78 mL, 0.671 mmole) and triphenyl phosphine (250mg, 0.951 mmole) are then added, followed by diethyl azodicarboxylate(120 mL, 0.761 mmole). After 3 hrs, the reaction mixture is filtered andsilica gel is added to the filtrate to adsorb the solutes and themixture is concentrated to dryness. The resulting solid mixture ispoured onto the top of a flash silica column which is eluted withhex:EtOAc (1:1 to 0:1) to give the desired white solid. CI⁺ MS: m/z (relintensity) 408 (M⁺+H, 15), 238 (100), 128 (99), 109 (93).

b.(1N)-4-Methoxyphenylsulfonamido-(2R)-N-hydroxycarboxamido-(4S)-mercaptophenylpyrrolidine:The starting methylester 14a (169 mg, 0.415 mmole) is taken in 1 mL ofmethanol, treated with NH₂OK (0.725 mL, 0.86 M in methanol solutionprepared as described in Fieser and Fieser, Vol 1, p 478) and stirredovernight. The following morning, dry silica (1.5 mL) is added to themixture and the solvent removed under vaccuum. The dry silica is pouredon the top of a flash silica gel column which is subsequently elutedwith hexane:EtOAc (1:1 to 0:1) and then with EtOAc:MeOH:NH₄OH (9:1:0.1)to give a white solid. ESI MS: m/z (rel intensity) 409.2 (M⁺+H, 100),426.2 (M⁺+NH₄, 12), 431.1 (M⁺+Na, 25).

Example 15

a.(1N)-4-Methoxyphenylsulfonamido-(2R)-carbomethoxy-(4R)-methane-sulfonyl-pyrrolidine:The starting alcohol 1a (17.9 g, 57 mmole) is taken in dry CH₂Cl₂ (100mL) in the presence of Et₃N (25 mL) at room temperature. Methanesulfonylchloride (4.87 mL, 63 mmole) is added dropwise and the resulting mixtureis seared overnight and the following morning the mixture is partionedbetween water and EtOAc. The organic layer is washed with brine, driedover MgSO₄, filtered and evaparated. The resulting solid isrecrystallized from EtOAc:hexanes to give the title compound as whiteprisms. CI⁺ MS: m/z (rel intensity) 411 (M+NH₄ ⁺, 25) 394 (M⁺+H, 21),224 (82), 155 (23), 128 (100).

b.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-(4-methoxy-mercaptophenyl)-pyrrolidine:The starting mesylate 15a (267 mg, 0.68 mmole) and 4-methoxythiophenol(88 ml, 0.713 mmole) are taken in THF (4 mL) at room temperature underargon and ^(t)butoxide (78 mg, 0.713 mmole) is added. The mixture isstirred for 1 hr and then partitioned between EtOAc and 1N HCl. Theorganic layer is washed with brine, dried over MgSO₄, filtered andevaporated to give 354 mg of residue which is then chromatographed overflash silica with hexane:EtOAc (8:1 to 2:1) to give the title compoundas a clear oil. CI⁺ MS: m/z (rel intensity) 438 (M⁺+H, 50), 268 (100),208 (21), 155 (81), 128 (79), 109 (45).

c.(1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-(4-methoxyphenyl-thioloxy)-pyrrolidine:The starting methylester 15b (129 mg, 0.295 mmole) is taken in 1 mL ofmethanol, treated with NH₂OK (0.85 mL, 0.86 M in methanol, solutionprepared as described in Fieser and Fieser, Vol 1, p 478) and stirredovernight. The following morning, dry silica (1.5 mL) is added to themixture and the solvent removed under vaccuum. The dry silica is pouredon the top of a flash silica gel column which is subsequently elutedwith hexane:EtOAc (1:2 to 0:1) to give a clear glass which is puffedinto a foamy solid by slight heating under vacuum. ESI MS: m/z (relintensity) 439 (M⁺+H, 100), 456 (M⁺+NH₃, 30).

Example 16

a.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-(3-methoxy-mercaptophenyl)-pyrrolidine:The starting mesylate 15a (267 mg, 0.68 mmole) and 3-methoxythiophenol(88 mL, 0.713 mmole) are taken in THF (4 mL) at room temperature underargon and ^(t)butoxide (78 mg, 0.713 mmole) is added. The mixture isstirred for 1 hr and then partitioned between EtOAc and 1N HCl. Theorganic layer is washed with brine, dried over MgSO₄, filtered andevaparated to give a residue which is then chromatographed over flashsilica with hexane:EtOAc (8:1 to 2:1) to give the title compound as aclear oil. CI⁺ MS: m/z (rel intensity) 438.0 (M+H⁺, 17), 268.0 (100),155 (65).

b.(1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-(3-methoxy-mercaptophenyl)-pyrrolidine:The starting methylester 16a (1.58 mg, 0361 mmole) is taken in 5 mL ofmethanol, treated with NH₂OK (0.624 mL, 0.86 M in methanol, solutionprepared as described in Fieser and Fieser, Vol 1, p 478) and stirredovernight. The following morning, dry silica (2 mL) is added to themixture and the solvent removed under vaccuum. The dry silica is pouredon the top of a flash silica gel column which is subsequently elutedwith hexane:EtOAc (1:1 to 0:1) then with EtOAc:MeOH:NH₄OH (9:1:0.1) togive a white solid. ESI MS: m/z (rel intensity) 439 (M⁺+H, 10), 456.0(M⁺+NH₄ ⁺, 40), 461.0 (M⁺+Na⁺, 27).

Example 17

a.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4R)-ethyloxymethoxy-pyrrolidine:Chloroethylmethylether (0.884 mL, 9.54 mmole) was added dropwise to astirred solution of the methylester 1a (1.00 g, 3.18 mmole) in CH₂Cl₂(12 mL) and DIPEA (0.830 mL) and stirred for 16 hrs. Additional CH₂Cl₂was added and the mixture was washed with saturated NaHSO₄, dried oversodium sulfate and the solvent removed under vacuum. The dried materialwas purified over a silica column eluting fist with hexane:EtOAc (8:2),followed with hexane:EtOAc (1:1) then with EtOAc to give a colorlessoil. ESI MS: m/z (rel intensity) 374.02 (M⁺+H, 100), 391.03 (M⁺+NH₃,70).

b.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4R)-ethyloxymethoxy-pyrrolidine:The starting methyl ester 17a (1.13 g, 3.03 mmole) is taken in 4 mL ofmethanol:tetrahydrofuran (1:1), and treated with NH₂OK (4 mL, 1.25M inmethanol) and stirred overnight. The following morning, dry silica (2.5mL) is added to the mixture and the solvent removed under vacuum. Thedry silica is poured on top of a flash silica column which issubsequently eluted with ethyl acetate followed with ethylacetate:methanol (8:2) to give a clear glass which is puffed to a foamysolid by slight heating under vacuum. The product was recrystallizedfrom cold EtOAc:hexane to give white powder. ESI MS: m/z (rel intensity)374.02 (M⁺+H, 100), 391.03 (M⁺+NH₃, 70).

Example 18

a.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4R)-benxyloxy-methoxy-pyrrolidine:Benzylchloromethylether (2.25 g, 9.54 mmole) is added dropwise to astirred solution of the methylester 1a (1.00 g, 3.18 mmole) in CH₂Cl₂(12 mL) and DIPEA (0.830 mL, 4.77 mmole) and stirred for four days.Additional CH₂Cl₂ is added and the mixture washed with saturatedNaH₂SO₄, dried over sodium sulfate and the solvent removed under vacuum.The dried material is purified over a silica column eluting first withhexane, then with hexane:EtOAc (7:3) to give a colorless oil.

ESI MS: m/z (rel intensity) 436.07 (M⁺+H, 100), 453.09 (M⁺+NH₃, 70).

b.(1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4R)-benxyl-oxymethoxy-pyrrolidine:The starting methyl ester 18a (1.00 g, 2.29 mmole) is taken in 2 ml ofmethanol/tetrahydrofuran (1:1), and treated with NH₂OK (2 ml, 1.25M inmethanol) and stirred overnight. The following morning, dry silica (1.5ml) is added to the mixture and the solvent removed under vacuum. Thedry silica is poured on top of a flash silica column which issubsequently eluted with hexane:ethyl acetate (7:3) followed with ethylacetate to give a clear glass which is dried to a foamy solid by slightheating under vacuum. The product was recrystallized from cold methanolto give white powder. ESI MS: m/z (rel intensity) 436.98 (M⁺+H, 100),453.97 (M⁺+NH₃, 30).

Example 19

a.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4R)-(2-methoxyethyl-oxy)-methoxypyrrolidine:MEM chloride (1.09 mL, 9.54 mmole) is added dropwise to a stirredsolution of the alcohol 1a (1.00 g, 3.18 mmole) in CH₂Cl₂ (12 mL) andDIPEA (0.830 mL) and stirred for 16 hrs. Additional CH₂Cl₂ is added andthe mixture is washed with saturated NaH₂SO₄, dried over sodium sulfateand the solvent removed under vacuum. The dried material was purifiedover a silica column eluting first with hexane:EtOAc (1:1) to give acolorless oil. ESI MS: m/z (rel intensity) 403.99 (M⁺+H, 70), 421.01(M⁺+NH₃, 100).

b.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4R)-(2-methoxyethyl-oxy)-methoxypyrrolidine:The starting methyl ester 19 (450 mg, 1.12 mmole) is taken in 2 mL ofmethanol:tetrahydrofuran (1:1), and treated with NH₂OK (2 mL, 1.25M inmethanol) and stirred overnight. The following morning, dry silica (1.5mL) is added to the mixture and the solvent removed under vacuum. Thedry silica is poured on top of a flash silica column which issubsequently eluted with EtOAC followed with ethyl acetate:methanol(8:2) to give a clear glass which is puffed to a foamy solid by slightheating under vacuum. The product was recrystallized from coldEtOAc:hexane to give white powder. ESI MS: m/z (rel intensity) 405.05(M⁺+H, 100), 422.01 (M⁺+NH₃, 20).

Example 20

a.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-thioacetoxyl-pyrrolidine:Triphenylphosphine (0.9 g, 3.42 mmole) is dissolved in 12 mL of THF.Diethyl azodicarboxylate (0.54 mL, 3.42 mmole) is added dropwise at 0°C. After 30 min with stirring, a solution of thioacetic acid (0.4 mL,5.13 mmole) and the alcohol 1a (0.54 g, 1.71 mmole) in 10 mL of THF isadded dropwise. The reaction is stirred at 0° C. for 30 min., roomtemperature for 2 hr and concentrated to an oil. The crude material ispurified by flash chromatography (CH₂Cl₂:hexane (1:1) to CH₂Cl₂:EtOAc;(50:1) to CH₂Cl₂:EtOAc; 25:1) on silica gel to give the desired product.ESI MS: m/z (rel intensity) 391 (100, M⁺+NH₃), 374 (65, M⁺+H).

b.(1N)-4-Methoxyphenylsulfonyl-(2R)-hydroxycarboxamido-(4S)-thio-pyrrolidine:The thioester 20a (0.4 g, 1.07 mmole) is dissolved in 2 mL of methanoland degassed by argon. A solution of NH₂OK (6.1 mL, 1.7 M in methanol,solution prepared as, described in Fieser and Fieser, Vol 1, p 478) isalso degassed and added to the thioester solution. After 2 hr withstirring, the reaction is acidified with 1N HCl, concentrated to removesolvent, then distributed between HCl and ethyl acetate. The ethylacetate layer is washed with brine, dried over MgSO₄ and concentrated toan oil. The crude product is purified by flash chromatography (1% formicacid in EtOAc) on silica gel to give the desired product ESI MS: m/z(rel intensity) 333 (90, M⁺+H).

Example 21

a.(±)-(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(3S)-phenyl-pyrrolidine:(±)-trans-3-phenylproline (403 mg, 1.73 mmole, prepared as described inJ. Med. Chem. 1994, 37, 4371.) is dissolved in water:dioxane (1:1, 5 mL)with triethylamine (0.6 mL, 433 mmole). 4-Methoxyphenylsulfonyl chloride(393 mg, 1.9 mmole) is added along with 2,6-dimethylaminopyridine(catalytic) and the mixture is stirred 14 hr. at room temperature. Themixture is then concentrated and diluted with EtOAc. Layers areseparated and the organic layer is washed 2× with 1N HCl, 1× with brine,dried over MgSO₄, filtered and evaparated to give 623 mg of solidmaterial which is dissolved in MeOH (15 mL). Thionyl chloride (1.5 mL)is added dropwise and the relating mixture stirred for 14 hr. Silica gel(4 mL) is added and the mixture concentrated. The resulting powder ispoured onto a flash silica column and eluted with hexane:EtOAc (1:1 to0:1) to give the title compound. ESI MS: m/z (rel intensity) 376.1(M⁺+H, 100), 316.1 (22).

b.(±)-(1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(3S)-phenylpyrrolidine:The methylester 21a (0.262 g, 0.699 mmole) is taken in 1 mL of methanol,treated with NH₂OK (1.2 mL, 0.86 M in methanol, solution prepared asdescribed in Fieser and Fieser, Vol 1, p 478) and stirred overnight. Thefollowing morning, dry silica (2 mL) is added to the mixture and thesolvent removed under vaccuum. The dry silica is poured on the top of aflash silica gel column which is subsequently eluted withhexane:EtOAc:HCO₂H (2:1 to 0:1) to give pure white solid which isrecrystallized from CHCl₃:hexane (3:1) to give white crystals. ESI MS:m/z (rel intensity) 377.1 (M⁺+H, 100), 394.1 (M⁺+NH₃, 22).

Example 22

a. (1N)-4-Methoxyphenylsulfonyl-(2R)-carboxy-(4R)-hydroxy-pyrrolidine:cis-Hydroxy-D-proline (10 g, 0.38 mole) is dissolved in water:dioxane(1:1, 60 mL) with triethylamine (25 mL). 4-Methoxyphenylsulfonylchloride (17.4 g, 0.084 mole) is added along with2,6-dimethylaminopyridine (0.92 g, 0.008 mole) and the mixture isstirred 14 hr. at room temperature. The mixture is then concentrated anddiluted with EtOAc. Layers are separated and the organic layer is washed2× with 1N HCl, 1× with brine, dried over MgSO₄, filtered and evaparatedto give the title compound. ESI MS: 302.2 (M⁺+H, 100), 319.3 (M⁺+NH₄,85).

b. (1N)-4-Methoxyphenylsulfonyl-(2R)-carboxy-4-oxo-pyrrolidine: A 0.76 Mbatch of Jones' reagent is prepared. The carboxyalcohol 22a (10.0 g,31.7 mmoles) is dissolved in 175 mL of acetone and cooled to 0° C.Jone's reagent is added (420 mL, 317 mmoles) and this is stirred at roomtemperature for 14 hr. The reaction mixture is diluted with water andextracted 3× with EtOAc. The organic layers are washed 3× with water and1× with sodium chloride, dried over magnesium sulfate, and evaporated.the material is recrystallized from Hex:EtOAc to give the pure ketoacid.ESI MS: 300.3 (M⁺+H, 93), 317.3 (M⁺+NH₄, 100).

c.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4,4)-(R)-hydroxy-ethylpyrrolidine:The ketone 22b (0.500 g, 1.67 mmole) is taken in 10 mL of THF and cooledto −15° C. Ethylmagnesium bromide (3.67 ml, 1M in THF, 3.67 mmole) isadded to this mixture. The mixture is sired for 30 min at which time itis partitioned between 1N HCl and EtOAc. The organic layer is washedwith brine, dried over magnesium sulfate, filtered and evaparated. Thecrude material is then sired overnight in methanol with 0.5 mL of SOCl₂and evaparated to dryness. The crude material is chromatographed overflash silica with hex:EtOAc (1:1) to give the pure title compound. ESIMS: 363.3 (M⁺+NH₄, 45), 346.3 (M⁺+H, 100).

d.(1N)-4-(Methoxyphenylsulfonyl-(2R)-hydroxy-carboxamido-(4,4)-(R)-hydroxy-ethylpyrrolidine:The methylester 22e (431 mg, 1.26 mmole) is taken in 1 mL of methanol,treated with NH₂OK (2 mL, 0.86 M in methanol, solution prepared asdescribed in Fieser and Fieser, Vol 1, p 478) and stirred overnight. Thefollowing morning, dry silica (2 mL) is added to the mixture and thesolvent removed under vaccuum. The dry silica is poured on the top of aflash silica gel column which is subsequently eluted withhexane:EtOAc:HCO₂H (2:1 to 0:1) to give pure white solid which isrecrystallized from CHCl₃:hexane (3:1) to give white crystals. ESI MS:362.2 (M⁺+NH₃, 60), 345.2 (M⁺+H, 100), 327.2 (15).

Example 23

a.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4,4)-(R)-gem-hydroxy-phenylpyrrolidine:The keto acid 22b (441 mg, 1.47 mmole) is treated with phenyl-magnesiumbromide (3.7 mL, 3.7 mmole) as described for 22c to give a blackresidue. This is then treated with K₂CO₃ (760 mg, 5.5 mmole) and MeI(0.343 mL, 5.5 mmole) in 10 mL of DMF for 45 min. This mixture is thenpartitioned between EtOAc and brine. The organic layer is then driedover MgSO₄, filtered and evaparated. The crude residue is thenchromatographed over flash silica with hexane:EtOAc (9:1 to 7:3) to givethe title compound as a brown oil. CI⁺ MS: m/z (rel intensity) 409.4(M+NH₄ ⁺, 100), 392.4 (M⁺+H, 75), 374.4 (65), 204.2 (72).

b.(1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4,4)-(R)-gem-hydroxyphenylpyrrolidine:The ester 23a (174 mg, 0.445 mmole) is converted to the title hydroxamicacid as described for 22d. ESI MS: m/z (rel intensity) 410.6 (M+NH₄ ⁺,100), 393.4 (M⁺+H, 75), 375.5 (65).

Example 24

a. (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-(4-octyl)phenoxycyclobutylamine: Triphenylphosphine (2.5 g, 9.51 mmole) was dissolved in20 mL of THF, diethyl azodicarboxylate (1.9 mL, 9.51 mmole) was addeddropwise at 0° C. After 30 min with stirring., a solution of4-octylphenol (2.46 g, 11.9 mmole) and the alcohol 1a (1.5 g, 4.76mmole) in 20 mL of THF was added dropwise. The reaction was stirred at0° C. for 30 min, room temperature overnight and concentrated to an oil.The crude product was purified by flash chromatography (hexane/EtOAc,1:1) on silica gel to give the desired product CI⁺ MS: m/z (relintensity) 504 (44, M⁺+H), 334 (100).

b.(1N)-4-Methoxyphenylsulfonamido-(2R)-hydroxycarboxamido-(4S)-(4-octyl)phenoxypyrrolidine:The methyl ester 24a (1.1 g, 2.1 mmole) was taken in 1 mL of methanol,treated with NH₂OK (8 ml, 1.7 M in methanol, solution prepared asdescribed in Fieser and Fieser, Vol 1, p 478) and stirred for 30 hr.Silica (1.5 mL) was added to the mixture and the solvent was removedunder vacuum. The dry silica was poured on the top of a flash silica gelcolumn which was subsequently eluted with EtOAc:CH₃OH (95:5 to 90:10) togive 0.6 g (61% yield) of desired product as a white foamy solid. ESIMS: m/z (rel intensity) 527 (30, M⁻+Na), 522 (25, M⁺+NH₄), 505 (100,M⁻+H).

Example 25

a. (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-4-oxopyrrolidine: A0.76 M batch of jone's reagent was prepared. The alcohol 1a (10.0 g,31.7 mmoles) was dissolved in 175 mL of acetone and cooled to 0° C.Jone's reagent was added (420 mL, 317 mmoles) and this was stirred atroom temperature for 14 hr. The reaction mixture was diluted with waterand extracted 3× with EtOAc. The organic layers were washed 3× withwater and 1× with sodium chloride, dried over magnesium sulfate, andevaporated. Chromotography was to performed on silica gel usingEtOAc:hexane (1:1) to give pure compound. Starting material was alsorecovered. CI⁺ MS: m/z (rel intensity) 314.0 (M⁺+H, 106).

b.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-3,3-dimethyl-4-oxopyrrolidine:A solution of potassium bis(trimethylsilyl)amide (0.5 M, 10.2 mmole) in20.5 mL of toluene is cooled to 0° C. under argon atmosphere and chargedwith 10 mL of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone. Themixture is cooled to −78° C. A solution of the substrate 25a (800 mg,2.56 mmole) in 20 mL of TRY is then added dropwise and the resultingmixture is stirred for 1 hr. Iodomethane (1.59 mL, 25.6 mmole) is thenadded and the reaction is stirred at −78° C. and then patitioned betweenEtOAc and dil. KHSO₄. The organic layer is then washed with brine, driedover. MgSO₄, filtered and evaperated. The crude oil is thenchromatographed over flash silica with hex:EtOAc (3:1 to 1:1) to givethe title compound. CI⁺ MS: m/z (rel intensity) 359 (M+NH₄ ⁺, 17), 342(M⁺+H, 20), 172 (100).

c.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-3,3-dimethyl-(4R)-hydroxypyrrolidine:The starting ketone 25b (241 mg, 0.70 mmole) is taken in 5 mL of medaland treated with NaBH₄ (42 mg, 1.05 mmole) at room temperature. The miteis stirred at rt for 1 hr, quenced with 1N HCl, and partitioned between1N HCl and EtOAc. The mixture is then partitioned between 1N HCl andEtOAc. The organic layer is washed with brine, dried over MgSO₄,filtered and concentrated. The crude oil is chromatographed over ahsilica to give the title compound as a cleat syrup. The ¹H NMR indicatesa (10:1) diastereomeric mixture. ESI MS: m/z (rel intensity): 346 (M⁺+H,100), 363 (M⁺+NH₃).

d.(1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-3,3-dimethyl-(4R)-hydroxypyrrolidine:The starting ester 25c (90 mg, 0.26 mmole) is converted to the titlecompound as described for 22d. ESI MS: m/z (rel intensity): 345.2 (M⁺+H,100), 362.2 (M⁺+NH₃), 65), 383.1 (M⁺+K, 55).

Examples 26-41

In the following examples W and Z are hydrogen, and Y is OH, n is 1, Aris substituted or unsubstituted phenyl, and X and Q refer tosubstituents on the phenyl ring:

Example X Q Y 26 Me H a-OH 27 OMe 3-OMe a-OH 28 OMe 2-NO₂ a-OH 29O(n-Bu) H a-OH 30 O(n-Bu) H b-OH 31 Br H a-OH 32 Br 3-Me a-OH 33 Cl 2-Cla-OH 34 OCH₂CH₂OCH₃ H a-OH 35 OPh H a-OH 36 OCH(CH₃)₂ H a-OH 37 Br 2-Meb-S(3-C₆H₄OMe) 38 O(n-Bu) H b-2-mercaptobenzo-thiazole 39 OMe 2-NO₂b-2-mercaptobenzo-thiazole 40 O(n-Bu) H b-S(4-C₆H₄OMe) 41 O(n-Bu) HO-(3-pyridyl)Me=methylEt=ethylBu=butyl

Example 26

a.(1N)-4-Methylphenylsulfonyl-(2R)-carbomethoxy-(4R)-hydroxy-pyrrolidine:Cis-Hydroxy-D-proline methylester (303 mg, 2.09 mmole) is dissolved inDMF (3 mL) and N-methyl morpholine (1 mL) and stirred under air for 14hr at room temperature in the presence of p-toluenesulfonyl chloride(418 g, 2.19 mmole). The mixture is then partitioned between EtOAc and1N HCl. The layers are separated and the organic layer is washed 1× with1N HCl, 1× with brine, dried over MgSO₄, filtered and condensed to give341 mg of crude material which is chromatographed over flash silica withhexane:MeOH (19:1) to give the desired material as a white solid. CI⁺MS: m/z (rel intensity) 300 (M⁺+H, 60), 240 (28), 146 (88), 126 (100).

b.(1N)-4-Methylphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-hydroxy-pyrrolidine:The methylester 26a (144 mg, 0.482 mmole) is taken in 1 mL of methanol,treated with NH₂OK (0.61 mL, 0.86 M in methanol, solution prepared asdescribed in Fieser and Fieser, Vol 1, p 478) and stirred overnight. Thefollowing morning the material is concentrated and partitioned betweenEtOAc and 1N HCl. The organic layer is washed with brine, dried overMgSO₄, filtered and evaparated to give 134 mg of crude material which ischromatographed over flash silica with EtOAc:MeOH (10:1) to give desiredproduct which is then recrystallized to give the desired white solid ESIMS: m/z (rel intensity) 301.0 (M+H⁺, 100), 318.0 (M+NH₄ ⁺, 35), 322.8(M+Na⁺, 70).

Example 27

a.(1N)-3,4-Dimethoxyphenylsulfonyl-(2R)-carbomethoxy-(4R)-hydroxy-pyrrolidine:Cis-Hydroxy-D-proline methyl ester (2.71 g, 18.7 mmole) is dissolved inDMF (10 mL) and N-methyl morpholine (5 mL) and stirred under air for 14hr at room temperature in the presence of 3,4-dimethoxyphenyl-sulfonylchloride (4.65 g, 19.6 mmole). The mixture is then partitioned betweenEtOAc and 1N HCl. The layers are separated and the organic layer iswashed 1× with 1N HCl, 1× with brine, dried over MgSO₄, filtered andcondensed to give 3.98 g of crude material which is chromatographed overflash silica with hexane:EtOAc (2:1 to 1:4) to give the desired materialas a white solid CI⁺ MS: m/z (rel intensity) 346 (M⁺+H, 100), 286 (20),146 (15).

b.(1N)-3,4-Dimethoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4R)-hydroxypyrrolidine:The methylester 27a (250 mg, 0.724 mmole) is taken in 5 ml-of methanoltreated with NH₂OK (1.25 mL, 0.86 M in methanol, solution prepared asdescribed in Fieser and Fieser, Vol 1, p 478) and stirred overnight. Thefollowing morning, dry silica (1.5 mL) is added to the mixture and thesolvent removed under vaccuum. The dry silica is poured on the top of aflash silica gel column which is subsequently eluted with hexane:EtOAc(1:1 to 0:1) to give a white foamy solid. ESI MS: m/z (rel intensity)347.0 (M⁺+H, 100), 369.1 (M⁺+Na, 45).

Example 28

a.(1N)-(2-Nitro-4-methoxyphenylsulphonyl)-(2R)-carbomethoxy-(4R)-hydroxy-pyrrolidine:cis-Hydroxy-D-proline (3.02 g, 23.1 mmole) is dissolved in water:dioxane(1:1, 300 mL) with triethylamine (7.9 ml, 57.5 mmole).2-Nitro-4-methoxyphenylsulfonyl chloride (6.38 g, 25.4 mole) is addedalong with 2,6-dimethylaminopyridine (281 mg, 231 mmole) and the mixtureis stirred 14 hr. at room temperature. The mixture is then concentratedand diluted with EtOAc. Layers are separated and the organic layer iswashed 2× with 1N HCl, 1× with brine, dried over MgSO₄, filtered andevaparated to give 7.06 g of solid material which is dissolved in MeOH(100 mL). Thionyl chloride (10 mL) is added dropwise and the resultingmixture stirred for 14 hr. The mixture is then evaparated to dryness andtriturated with CHCl₃ to give a brownish solid which is sufficientlypure to carry forward without purification. CI⁺ MS: m/z (rel intensity)378 (M+NH₄ ⁺, 40), 361 (M⁻+H, 100), 331 (12), 301 (43), 144 (95).

b.(1N)-(2-Nitro-4-methoxyphenylsulfonyl)-(2R)-N-hydroxy-carboxamido-(4R)-hydroxypyrrolidine:The methylester 28a (300 mg, 0.833 mmole) is taken in 4 mL of methanoltreated with NH₂OK (1.44 mL, 0.86 M in methanol solution prepared asdescribed in Fieser and Fieser, Vol 1, p 478) and stirred overnight. Thefollowing morning, dry silica (2 mL) is added to the mixture and thesolvent removed under vaccuum. The dry silica is poured on the top of aflash silica gel column which is subsequently eluted with hexane:EtOAc(4:1) then with EtOAc:MeOH:NH₄OH (8:2:0.1) to give a white solid. ESIMS: m/z (rel intensity) 362.0 (M⁺+H, 100), 379.2 (M⁺+NH₄ ⁺, 7), 384.1(M⁺+Na⁻, 55).

Example 29

a.(1N)-(4-^(n)Butoxyphenylsulfonyl)-(2R)-carbomethoxy-(4R)-hydroxy-pyrrolidine:Cis-D-Hydroxyproline methyl ester (583 mg, 4.02 mmole) is dissolved inDMF (7 mL) and N-methyl morpholine (3 mL) and stirred under air for 14hr at room temperature in the presence of para-n-butoxyphenylsulfonylchloride (1.00 g, 4.02 mmole). The mixture is then partitioned betweenEtOAc and 1N HCl. The layers are separated and the organic layer iswashed 1× with 1N HCL, 1× with brine, dried over MgSO₄, filtered andcondensed to give 1.2 g of crude material which is chromatographed overflash silica with hexane:EtOAc (4:1 to 1:3) to give the material as awhite solid. CI⁺MS: m/z (rel intensity) 358 (M⁺+H, 100), 298 (23), 146(53), 114 (24).

b.(1N)-4-^(n)Butoxyphenylsulfonamido-(2R)-N-hydroxycarboxamido-(4R)-hydroxypyrrolidine:The methylester 29a (347 mg, 0.971 mmole) is taken in 2 mL of methanoltreated with NH₂OK (1.68 ml, 0.86 M in methanol solution prepared asdescribed in Fieser and Fieser, Vol 1, p 478) and stirred overnight. Thefollowing morning, dry silica (2 mL) is added to the mixture and thesolvent removed under vaccuum. The dry silica is poured on the top of aflash silica gel column which is subsequently eluted with hexane:EtOAc(4:1) then with EtOAc:MeOH:NH₄OH (4:1:0.1) to give a white solid. ESIMS: m/z (rel intensity) 359.1 (M⁺+H, 100), 381.1 (M⁺+Na, 45).

Example 30

a.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-benzoyl-pyrrolidine:The alcohol 29a (200 mg, 0.56 mmole) is dissolved in 1.5 mL of methylenchloride. Benzoic acid (82 mg, 0.672 mmole) and triphenyl phosphine (220mg, 0.84 mmole) are then added, followed by diethyl azodicarboxylate(106 mL, 0.672 mmole). After 3 hrs, the reaction mixture is filtered andsilica gel is added to the filtrate to adsorb the solutes and themixture is concentrated to dryness. The resulting solid mixture ispoured onto the top of a flash silica column which is eluted withhex:EtOAc (3:1 to 2:1) to give the desired product a white solid. CI⁺MS: m/z (rel intensity) 479.1 (M+NH₄ ⁺, 55), 462.0 (M⁺+H, 30), 250.0(100), 126 (38).

b.(1N)-4-^(n)Butoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-hydroxypyrrolidine:The methylester 30a (154 mg, 0.334 mmole) is taken in 2 mL of methanol,treated with NH₂OK (1.0 mL, 0.86 M in methanol, solution prepared asdescribed in Fieser and Fieser, Vol 1, p 478) and stirred overnight. Thefollowing morning, dry silica (1.5 mL) is added to the mixture and thesolvent removed under vaccuum. The dry silica is poured on the top of aflash silica gel column which is subsequently eluted with hexane EtOAc(1:1 to 0:1) and finally with EtOAc:MeOH:NH₄OH (9:1:0.1) to give a clearglassy solid. ESI MS: m/z (rel intensity) 359 (M⁺+H, 40), 376 (M+NH₄ ⁺,30), 381 (M+Na⁺, 20).

Example 31

a.(1N)-4-Bromobenzenesulfonyl-(2R)-carbomethoxy-(4R)-hydroxypyrrolidine:The title ester was prepared as described for compound 28a fromcis-hydroxy-D-proline (4.43 g, 35.1 mmole) and 4-bromobenzenesulfonylchloride. ESI MS: m/z (rel intensity) 364.0 (M⁺+H, 95), 366.0 (M⁺+H,95), 381.0 (M⁺+NH₃, 98), 383.0 (M⁺+NH₃, 100).

b.(1N)-4-Bromobenzenesulfonyl-(2R)-N-hydroxycarboxamido-(4R)-hydroxypyrrolidine:The title hydroxamic acid was prepared from ester 31a (7.59 g, 20.9mmole) as described for compound 25. The resulting material wasrecrystallized from EtOAc. ESI MS: m/z (rel intensity) 365.1 (M⁺+H, 98),367.1 (M⁺+H, 100), 382.2 (M⁺NH₄ ⁺, 45), 384.2 (M+NH₄ ⁺, 45).

Example 32

a.(1N)-2-Methyl-4-bromobenzenesulfonyl-(2R)-carbomethoxy-(4R)-hydroxypyrrolidine:The title ester was prepared as described for compound 28a fromcis-hydroxy-D-proline (361 mg, 2.76 mmole) and2-methyl-4-bromobenzenesulfonyl chloride. CI⁺ MS: m/Z (rel intensity)397 (M⁺+NH₃, 100), 395 (M⁺+NH₃, 95), 380 (M⁺+H, 50), 378 (M⁺+H, 45), 317(35), 300 (20), 146 (40).

b.(1N)-2-Methyl-4-bromobenzenesulfonyl-(2R)-hydroxycarboxamido-(4R)-hydroxypyrrolidine:The title hydroxamic acid was prepared form ester 32a (271 m& 0.72mmole) as described for compound 28. The resulting material wasrecrystallized from water. ESI MS: m/z (rel intensity) 398 (M⁺+NH₃, 85)396 (M⁺+NH₃, 80), 379(M⁺+H, 90), 381 (M⁺+H, 100).

Example 33

a. (1N)-2,4-Dichloro-(2R)-carbomethoxy-(4R)-hydroxypyrrolidine: Thetitle compound is prepared as described for compound 28a fromcis-hydroxy-D-proline (500 mg, 3.8 mmole)

a.(1N)-4-Phenoxyphenylsulfonyl-(2R)-carbomethoxy-(4R)-hydroxypyrrolidine:The title compound is prepared from cis-D-hydroxyproline (5.00 g, 38.1mmole) and phenoxyphenylsulfonyl chloride (11.2 g, 42 mmole, prepared asdescribed for R. J. Cremlyn et al in Aust. J. Chem., 1979, 32, 445.52)as described for compound 28a. The compound is purified over flashsilica with EtOAc:hexane (1:1 to 1:0) to give the title compound as aclear gum. CI⁺ MS: m/z (rel intensity) 378.11 (M⁺+H, 100), 395.11(M⁺+NH₃, 40).

b.(1N)-4-Phenoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4R)-hydroxypyrrolidine:The starting methyl ester 35a (864 mg, 2.30 mmole) is taken in 6 mL ofmethanol tetrahydrofuran (1:1), and treated with NH₂OK (3 ml, 1.25M inmethanol) and stirred overnight. The following morning, dry silica (1.5mL) is added to the mixture and the solvent removed under vacuum. Thedry silica is poured on top of a flash silica column which issubsequently eluted with ethyl acetate followed with ethylacetate:methanol (8:2) to give a clear glass which is puffed to a foamysolid by slight heating under vacuum. The product was recrystallizedfrom cold methanol to give the title compound as a white powder. ESI MS:m/z (rel intensity) 379.10 (M⁺+H, 100), 396.10 (M⁺+NH₃, 10).

Example 36

a. 4-(iso-butoxy)-phenylsulfonyl chloride: The title compound wasprepared as described for example 34a. ESI MS: m/z (rel intensity) 245.1(M⁺+H, 50), 262.1 (M⁺+NH₃, 100).

b.(1N)-4-iso-butyloxyphenylsulfonyl-(2R)-carbomethoxy-(4R)-hydroxypyrrolidine:The title ester was prepared from cis-hydroxy-D-proline (10.0 g, 76.3mmole) and sulfonyl chloride 36a (19.0 g, 763 mmole) as described forcompound 25a. ESI MS: m/z (rel intensity) 358.1 (M⁺+H, 100), 375.1(M⁺+Na, 45).

c.(1N)-4-iso-butyloxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4R)-hydroxypyrrolidine:The starting methyl ester 36b (1.5 g, 4.2 mmole) is taken in 7 mL ofmethanol, and treated with NH₂OK (7 mL, 1.25M in methanol) and sireovernight. A precipitate formed which is filtered and purified bypartioning between water and EtOAc. The organic layer is concentrated invacuo and recrystallized from hexane:EtOAc to give pure material. Theoriginal filtrate is dried and worked up like the filtrate and filteredthrough dry silica gel with EtOAc:MeOH (9:1) and the product was fromEtOAc:hexane to give additional product ESI MS: m/z (rel intensity)359.1 (M⁺+H, 100), 376.1 (M⁺+NH₄, 55), 381.1 (M⁺+Na, 15).

Example 37

a.1N)-2-Methyl-4-bromophenylsulfonyl-(2R)-carbomethoxy-(4S)-(3-methoxymercapto-phenyl)-pyrrolidine:The starting alcohol 32a (310 mg, 0.82 mmole) is taken in 5 mL of CH₂Cl₂and 1 mL of triethylamine and treated with methanesulfonyl chloride (76μL, 0.984 mmole). The solution is stirred for 1 hr at rt and thenpartitioned between EtOAc and 1N HCl. The organic layer was dried overMgSO₄, filtered and evaparated. The crude reside was then taken in 2.5mL of THF at rt under argon and treated first with ^(t)butoxide (50 mg,0.45 mmole) and then 3-methoxythiophenol (110 μL, 0.90 mmole). Themixture is stirred for 16 hr and then partitioned between EtOAc and 1NHCl. The organic layer is washed with brine, dried over Na₂SO₄, filteredand evaparated to give a residue which is then chromatographed overflash silica with hexane:EtOAc (4:1) to give the title compound as aclear glass. CI⁺ MS: m/z (rel intensity) 517, 519 (M⁺+NH₃, 92), 500, 502(M⁺+H, 48) 439 (30), 422 (20), 141 (50), 128 (100).

b.(1N)-2-Methyl-4-bromophenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-3-methoxymercapto-phenyl)-pyrrolidine:The methylester 37a (101 mg, 0.202 mmole) is taken in 2 mL ofmethanol:THF (1:1), treated with NH₂OK (2.0 mL, 1.25 M in methanol,solution prepared as described in Fieser and Fieser, Vol 1, p 478) andstirred overnight. The following morning, dry silica (1.5 mL) is addedto the mixture and the solvent removed under vaccuum. The dry silica ispoured on the top of a flash silica gel column which is subsequentlyeluted with EtOAc and then with EtOAc:MeOH (4:1) to give 79 mg (79%) ofa clear glassy solid ESI MS: m/z (rel intensity) 501, 503 (M⁺+H, 65),518, 520 (M⁺+NH₃, 100), 523, 525 (M⁺+Na, 35).

Example 38

a.(1N)-^(n)Butoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-(2-mercaptobenzothiazolyl)pyrrolidine:The alcohol 29a (200 mg, 0.56 mmole) is dissolved in 2.5 mL of methylenechloride. 2-Mercaptobenzothiazole (113 mg, 0.672 mmole) andtriphenyl-phosphine (220 mg, 0.84 mmole) are then added, followed bydiethyl azodicarboxylate (106 mL, 0.672 mmole). After 3 hrs, thereaction mixture is filtered and silica gel is added to the filtrate toadsorb the solutes and the mixture is concentrated to dryness. Theresulting solid mixture is poured onto the top of a flash silica columnwhich is eluted with hex:EtOAc (2:1 to 1:1) to give the desired productMS CI⁺: m/z (rel intensity) 507.0 (M+H⁺, 30), 359.1 (42), 342.0 (39),167.9 (100), 135.9 (90).

b.(1N)-4-^(n)Butoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-(2-mercaptobenzothiazolyl)-pyrrolidine:The methylester 38a (214 mg, 0.422 mmole) is taken in 1.5 mL ofmethanol, treated with NH₂OK (0.73 mL, 0.86 M in methanol, solutionprepared as described in Fieser and Fieser, Vol 1, p 478) and stirredovernight. The following morning, dry silica (2 mL) is added to themixture and the solvent removed under vaccuum. The dry silica is pouredon the top of a flash silica gel column which is subsequently elutedwith hexane:EtOAc (1:1 to 0:1) and finally with EtOAc:MeOH:NH₄OH(4:1:0.1) to give a white powder. ESI MS: m/z (rel intensity) 508 (M⁺+H,100), 532 (M⁺+Na, 32).

Example 39

a.(1N)-2-Nitro-4-methoxyphenylsulfonyl-(2R)-N-carbomethoxy-(4S)-(2-mercaptobenzothiazolyl)-pyrrolidine:The alcohol 28a (200 mg, 0.55 mmole) is dissolved in 1.5 mL of methylenechloride. 2-Mercaptobenzothiazole (112 mg, 0.66 mmole) and triphenylphosphine (219 mg, 0.833 mmole) are then added, followed by diethylazodicarboxylate (105 mL, 0.666 mmole). After 3 hrs, the reactionmixture is filtered and silica gel is added to the filtrate to adsorbthe solutes and the mixture is concentrated to dryness. The resultingsolid mixture is poured onto the top of a flash silica column which iseluted with hex:EtOAc (4:1 to 1:1) to give the desired product as awhite solid. CI⁺ MS: m/z (rel intensity) 509.9 (M⁺+H, 30), 315.0 (18),294.9 (18), 167.9 (100), 135.9 (95).

b.(1N)-2-Nitro-4-methoxyphenylsulfonyl-(2R)-N-hydroxy-carboxamido-(4S)-(2-mercapto-benzothiazolyl)-pyrrolidine:The methylester 39a (277 mg, 0.544 mmole) is taken in 1 mL of methanoltreated with NH₂OK (1.0 mL, 0.86 M in methanol, solution prepared asdescribed in Fieser and Fieser, Vol 1, p 478) and stirred overnight. Thefollowing morning, dry silica (2 mL) is added to the mixture and thesolvent removed under vaccuum. The dry silica is poured on the top of aflash silica gel column which is subsequently eluted with hexane:EtOAc(1:1 to 0:1) followed by EtOAc:MeOH:NH₄OH (9:1:0.1) to give the whitesolid. ESI MS: m/z (rel intensity) 511.1 (M⁺+H, 100), 533.0 (M⁺+Na, 30).

Example 40

a.(1N)-(4-^(n)butoxyphenylsulfonyl)-(2R)-carbomethoxy-(4S)-(4-methoxy-mercaptophenyl)-pyrrolidine:The alcohol 29a (178 mg, 0.499 mmole) is taken in 2 mL of CH₂Cl₂ and tothis mixture is added triphenylphosphene (157 mg, 0.599 mmole),4-methoxythiophenol (67 ml, 0.548 mmole), and diethyl-diazadicarboxylate(95 mM, 0.0.548 mmole) and the mixture is stirred for 3 hr. at whichtime 3 mL of silica gel is added to the mixture which is thenconcentrated to dryness. The dry residue is poured onto the top of aflash silica column and eluted with hexane:EtOAc (4:1 to 1:4) to give aclear oil. CI⁺ MS: m/z (rel intensity) 468 (M⁺+H, 48), 301 (43), 272(46), 187 (65), 109 (100).

b.(1N)-(4-Methoxyphenylsulfonyl)-(2R)-N-hydroxycarboxamido-(4S)-(4-methoxyphenyl-thioloxy)-pyrrolidine:The methylester 40a (125 g, 0268 mmole) is taken in 1 mL of methanol,treated with NH₂OK (0.465 mL, 0.86 M in methanol solution prepared asdescribed in Fieser and Fieser, Vol 1, p 478) and stirred overnight. Thefollowing morning, dry silica (2 mL) is added to the mixture and thesolvent removed under vaccuum. The dry silica is poured on the top of aflash silica gel column which is subsequently eluted with hexane:EtOAc(2:1 to 0:1) to give a white solid. ESI MS: m/z (rel intensity) 481(M⁺+H, 10), 498.1 (M+NH₄ ⁺, 100), 503.1 (M⁺+Na, 20).

Example 41

a.(1N)-4-^(n)Butoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-(3-pyridyloxy)-pyrrolidine:The title compound is prepared as described for 13a. CI⁺ MS: m/z (relintensity) 468 (M⁺+H, 48), 301 (43), 272 (46), 187 (65), 109 (100).

b.(1N)-4-^(n)Butoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-(3-pyridyloxy)-pyrrolidine:The title compound is prepared as described for 13b. ESI MS: m/z (relintensity) 436.1 (M⁺+H, 100), 458.1 (M+NH₄ ⁺, 60), 517.8 (M⁺+Na, 15).

Examples 42-61

In the following examples, W and Z are hydrogen, and Y is OH, n is 1, Aris substituted or unsubstituted phenyl, and X and Q refer tosubstituents on the phenyl ring:

Example X P R 42 OMe H H 43 OnBu H H 44 OMe H n-Pr 45 OMe H n-Hex 46 OMeH CH₂CH₂Ph 47 OMe n-Bu n-Hex 48 OMe H SO₂Me 49 On-Bu H SO₂Me 50 On-Bu HSO₂3-(N-methylimidazole) 51 OMe CH₂(3-pyridyl) SO₂Me 52 OMe SO₂Me SO₂Me53 OMe n-Pr SO₂Me 54 OMe H SO₂pC₆H₄OMe 55 OMe H COn-Pent 56 OMe HCOp-Ph-Ph 57 OMe H CONHMe 58 OMe H COCH(R-OBn)CH₃ 59 OMe HCOCH(R-OBn)CH₂Ph 60 OMe i-Pr COCH(R-OH)CH₃ 61 OMe i-Pr COCH(R-OH)CH₂Ph

Example 42

a. (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-azidopyrrolidine:The starting mesylate 15a (4.2 g, 10.7 mmole) is taken in 15 mL of dryDMF in the presence of NaN₃ (695 mg, 10.7 mmole). The resulting mixtureis heated to 55° C. for 26 hrs and then partitioned between water andEtOAc. The organic layer is then washed with brine, dried over MgSO₄,filtered and evaparated. The resulting crude oil is chromatographed overflash silica with hexane:EtOAc (5:1 to 3:1) to provide pale yellow oilwhich solidifies upon standing. CI⁺ MS: m/z (rel intensity) 358 (M+NH₄⁺, 50), 341 (M++H, 67), 315 (95), 145 (100).

b. (1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-aminopyrrolidine:The starting azide 42a (1.18 g, 3.48 mmole), is taken in 100 mL ofEtOH:THF:HCO₂H (5:1:0.1), and hydrogenated at rt. under 54 psi ofhydrogen in the presence of 100 mg of 10% Pd—C for 16 hrs. The mixtureis then filtered through a pad of celite, concentrated to, an oil andrecrystallized from hexane:EtOAc to give the desired product as theformate salt CI⁺ MS: m/z (rel intensity) 315 (M⁺+H, 12), 177 (13), 143(42), 123 (60), 109 (100).

c.(1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-aminopyrrolidine:The starting ester 42b (500 mg, 1.59 mmole), is taken in 5 mL of MeOH,treated with NH₂OK (1.92 mL, 0.86 M in methanol, solution prepared asdescribed in Fieser and Fieser, Vol 1, p 478) and stirred overnight. Thefollowing morning, dry silica (1.5 mL) is added to the mixture and thesolvent removed under vaccuum. The dry silica is poured on the top of aflash silica gel column which is subsequently eluted with EtOAc:MeOH(4:1 to 3:2) to give white solid. ESI MS: m/z (rel intensity) 3163(M⁺+H, 100), 3333 (M++NH₄, 15).

Example 43

a.(1N)-4-^(n)Butoxyphenylsulfonyl-(2R)-carbomethoxy-(4R)-methylsulfonoxy-pyrrolidine:The starting alcohol 1a (6.78 g, 19.0 mmole) is converted to the titlemesylate as described for compound 15a. CI MS: m/z (rel intensity) 453(M+NH₄ ⁺, 38), 336 (M⁺+H, 27), 224 (100), 128 (67).

b.(1N)-4-^(n)Butoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-azidopyrrolidine:The starting mesylate 43a (5.85 g, 13.5 mmole) is converted to the titleazide as described for compound 41a. ESI MS: m/z (rel intensity) 383.1(M⁺+H, 50), 400.1 (M⁺+NH₃, 100).

c.(1N)-4-^(n)Butoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-azidopyrrolidine:The starting azide 43b (4.65 g, 12.2 mmole), is taken in 200 mL of MeOHwith 20 mL of HOAc and hydrogenated at rt. under 54 psi of hydrogen inthe presence of 200 mg of 10% Pd—C for 16 hrs. The mixture is thenfiltered through a pad of celite, concentrated to an oil, taken in MeOHand stirred with ˜50 g of Amberlite IRA-68 basic resin preconditionedwith 0.1 N NaOH, water and MeOH), filtered through a glass frit andadsorbed onto a plug of silica. This is then eluted over a column offlash silica with EtOAc:MeOH (1:0 to 3:1) to give pale yellow oil whichsolidifies upon standing. CI MS: m/z (rel intensity) 357 (M⁺+H, 65), 145(100).

d.(1N)-4-Methoxyphenylsulfonyl-(2R)-hydroxycarboxamido-(4S)-amino-pyrrolidine:

The starting ester 43c (234 mg, 356 mmole), is converted to the titlecompound as described for compound 42c and then purified further byrecrystallizing from water to give white crystalls. ESI MS: m/z (relintensity) 358 (M⁺+H).

Example 44

a.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-propylamino-pyrrolidine:The starting amine 42b (810 mg, 2.6 mmole) is dissolved in 8 mL ofmethanol and stirred for 48 hrs in the presence of propianaldehyde (206mL, 2.86 mmole), sodium cyanoborohydride (180 mg, 2.86 mmole), sodiumacetate (810, 9.9 mmole) and 25 drops of acetic acid. The mixture isevaparated to dryness and then partitioned between dil. NaHCO₃ and EtOAcand the organic layer is washed 2 times with NaHCO₃, 1 time with brine,dried over MgSO₄, filtered and evaparated to give a gummy oil which wassufficiently clean to carry forward without further purification. ESIMS: m/z (rel intensity) 357.3 (M⁺+H, 100).

b.(1N)-4-Methoxyphenylsulfonyl-2R)-N-hydroxycarboxamido-(4S)-propylamino-pyrrolidine:The starting methylester 44a (11.3, g, 31.7 mmole) is taken in 30 mL ofmethanol treated with NH₂OK (38 mL, 1.25 M in methanol, solutionprepared as described in Fieser and Fieser, Vol 1, p 478) and stirredfor 16 hrs. The following morning, dry silica (30 mL) is added to themixture and the solvent removed under vaccuum. The dry silica is pouredon the top of a flash silica gel column which is subsequently elutedwith chloroform:methanol (8:2) to give a pale yellow solid which wastaken in methanol and stirred for 1 hr in the presence of activatedcharcoal and then filtered through celite and evaparated to give a whitesolid. ESI MS: m/z (rel intensity) 358.2 (M⁺+H, 100), 380.1 (M⁺+Na, 5).

Example 45

a.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-^(n)hexylamino-pyrrolidine:The starting alcohol 1 (300 mg, 0.951 mmole) is dissolved in 2 mL ofCH₂Cl₂ under argon and cooled to 0° C. 2,6-Lutidine (135 μL 1.14 mmole)is added via syringe followed by like addition oftrifluoro-methanesulfonyl anhydride (179 mL, 1.05 μmole). The mixture isstirred for 1 hr., followed by syringe addition of dry hexylamine (500μL, 3.80 mmol) and then the mixture is allowed to come to roomtemperature, stir for 14 hrs, and heat to reflux for 4 hrs. Silica gel(3 mL) is added and the mixture evaparated to dryness. The dry powder ispoured on the top of a column of flash silica gel which is then elutedwith hexane:EtOAc (2:1 Ø 1:1) to give a colorless, glassy solid. CI⁺ MS:m/z (rel intensity) 399 (M⁺+H, 38), 229 (100), 227 (62).

b.(1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-^(n)hexylamino)-pyrrolidine:The starting methylester 45a (88 mg, 0.221 mmole) is taken in 1 mL ofmethanol, treated with NH₂OK (0.381 mL, 0.86 M in methanol, solutionprepared as described in Fieser and Fieser, Vol 1, p 478) and stirredovernight. The following morning, dry silica (1.5 mL) is added to themixture and the solvent removed under vaccuum. The dry silica is pouredon the top of a flash silica gel column which is subsequently elutedwith hexane:EtOAc (1:1 Ø 0:1) to give a white foamy solid ESI MS: m/z(rel intensity) 400.3 (M⁺+H, 100), 422.2 (M⁺+Na, 12).

Example 46

a.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-2-phenylethyl-amino-pyrrolidine:The primary amine 42b (300 mg, 1 mmole) is N-alkylated withphenylacetaldehyde (0.13 mL, 1.1 mmole) as described for compound 44a togive the desired amine as a clear gum which was carried forward withoutfurther purification. CI⁺MS: m/z (rel intensity) 419 (M⁺+H, 38), 249(20), 249 (19).

b.(1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-2-phenylethyl-aminopyrrolidine:The starting ester 46a (490 mg, 1 mmole) is converted to the titlecompound as described for compound 45b and purified over flash silicawith EtOAc:MeOH (4:1) to give a white solid. ESI MS: m/z (rel intensity)420.4 (M⁺+H, 100).

Example 47

a.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-N,N-^(n)butyl,^(n)hexylamino-pyrrolidine:The starting amine 45a (100 mg, 0.251 mmole) was converted to 93 mg (82%h) of the title compound as described for compound 44a. CI⁺ MS: m/z (relintensity) 470 (M⁺+H, 10), 299 (20), 242 (100).

b.(1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-N,N-^(n)butyl,^(n)hexylamino-pyrrolidine:The starting ester 47a (80.5 mg, 0.172 mmole) was converted to 56 mg(69%) of the title compound as described for compound 44b. CI⁺ MS: m/z(rel intensity) 469 (M⁺+H, 42), 299 (100), 242 (28), 172 (46).

Example 48

a.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-methanesulfonyl-aminopyrrolidine:The primary amine 42b (502 mg, 1.60 mmole) is taken in 5 mL of methylenechloride and 0.5 mL of triethyl amine and treated with methanesulfonylchloride (200 μL, 2.58 mmole) via syringe. The mixture is stirred for 2hr and then partitioned between 1N HCl and EtOAc. The organic layer waswashed with brine, dried over MgSO₄, filtered and evaporated to give 684mg of crude material which was chromatographed over flash silica withhexane EtOAc (2:1 to 1:1) to give disulfonylated material 51a andmonosulfonylated material 47a. CI⁺MS: m/z (rel intensity) 410 (M⁺+NH₄,15), 393 (M⁺+H, 10), 203 (100).

b.(1N)-4-Methoxyphenylsulfonyl-(2R)-hydroxycarboxamido-(4S)-methane-sulfonylaminopyrrolidine:The starting ester 48a (354 mg, 0.903 mmole) is converted to the titlecompound and chromatographed as described for compound 45b. It is thenrecrystallized from acetonitrile/water to give pale yellow crystals. ESIMS: m/z (rel intensity) 394 (M⁺+H, 60), 411 (M⁺+NH₄, 100).

Example 49

a.(1N)-4-^(n)Butoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-methanesulfonyl-aminopyrrolidine:The primary amine 43c (21.3 g, 60 mmole) is taken in 120 mL of methylenechloride and 36 mL of triethyl amine and treated dropwise withmethanesulfonyl chloride (5.1 mL, 66 mmole) at 0° C. The mixture isallowed to come to room temperature for 1 hr and then adsorbed ontosilica, evaparated to dryness, and eluted through a column of flashsilica with hexane:EtOAc (4:1 to 1:1) to give the title compound. ESIMS: m/z (rel intensity) 452 (M⁺+NH₃, 12), 435 (M⁻+H, 9), 223 (100).

b.(1N)-4-^(n)Butoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-methane-sulfonylaminopyrrolidine:The starting ester 49a (21.4 g, 49.2 mmole) is taken in 60 mL ofmethanol:THF (1:1), treated with NH₂OK (59 mL, 1.25 M in methanol,solution prepared as described in Fieser and Fieser, Vol 1, p 478) andstirred overnight. The following morning, dry silica (45 mL) is added tothe mixture and the solvent removed under vaccuum. The dry silica ispoured on the top of a flash silica gel column which is subsequentlyeluted with hexane:EtOAc (1:1 Ø 0:1), then EtOAc:methanol (9:1) to givea white foamy solid. This material was heated to 60° C. for 48 hrs and awhite, solid impurity sublimed off leaving behind light yellow powder.ESI MS: m/z (rel intensity) 453.08 (M⁺+NH₃, 50), 436.05 (M⁺+H, 100).

Example 50

a.(1N)-4-n-Butoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-[(1N)-methyl-3-imidazolyl]-sulfonylamino-pyrrolidine:The primary amine 43c (232 mg, 0.906 mmole) is taken in 3 mL ofmethylene chloride and 0.5 mL of triethyl amine and treated with1N-methyl-3-imidazoyl-sulfonyl chloride (280 mg, 1.55 mmole) at rt. Themixture is allowed to stir for 16 hr and then adsorbed onto silica,evaporated to dryness, and eluted through a column of flash silica withhexane:EtOAc (1:1 to 0:1) to give the title compounds as a clear oilwhich contained ˜20 mole percent of the starting sulfonyl chloride. Thismaterial was carried forward without further purification. ESI MS: m/z(rel intensity) 501 (M⁺+H, 70), 357 (45), 289 (82), 162 (100).

b.(1N)-4-n-Butoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-[(1N)-methyl-3-imidazolyl]-sulfonylamino-pyrrolidine:The starting ester 50a (236 mg, 0.471 mmole) is converted to the titlecompound and chromatographed as described for compound 45b to give 262mg of yellow oil which was further purified by reverse phase prep. HPLCto give pure solid. ESI MS: m/z (rel intensity) 502.2 (M⁺+H).

Example 51

a.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-N-(3-pyridyl)methylaminopyrrolidine:The primary amine 42b (810 mg, 2.6 mmole) is N-alkylated with3-pyridine-carboxaldehyde (270 μL, 2.86 mmole) as described for compound44a to give the desired amine as a clear gum which is purified overflash silica gel with EtOAc:MeOH (1:0 to 9:1) to give white solid. CIMS: m/z (rel intensity) 406 (M⁺+H, 100), 236 (45), 234 (48).

b.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-N,N-(3-pyridylmethyl)-(methanesulfonyl)aminopyrrolidine:The secondary amine 51a (7.80 mg, 19.3 mmole) is taken in 85 mL ofmethylene chloride and 11 mL of triethyl amine with a catalytic amountof 2,5-dimethylamino-pyridine and treated with methanesulfonyl chloride(4.5 mL, 57.8 mmole) at rt. The mixture is allowed to stir for 16 br andthen adsorbed onto silica, evaparated to dryness, and eluted through acolumn of flash silica with EtOAc:MeOH (0:1 to 9:1) to give the titlecompound as a yellow foamy solid. CI MS: m/z (rel intensity) 484 (M⁺+H,30), 406 (10), 314 (40), 234 (90), 187 (42), 102 (100).

c.(1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-N,N-(3-pyridylmethyl)-(methanesulfonyl)-aminopyrrolidine:The starting ester 51b (6.33 g, 13.1 mmole) is converted to the relativehydroxamic acid as described for compound 45b and eluted through flashsilica with EtOAc:MeOH (1:0 to 4:1) to give the title compound as awhite powder. ESI MS: m/z (rel intensity) 484.9 (M⁺+H, 100), 506.9(M⁺+NH₃, 10).

Example 52

a.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-bis-(N-methanesulfonyl)-amino-pyrrolidine:The title compound is isolated from the crude mixture in 48a. ESI MS:m/z (rel intensity) 488.3 (M⁺+NH₄ ⁺, 15), 471.3 (M⁺+H, 10).

b.(1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-bis-(N-methanesulfonyl)-amino-pyrrolidine:The starting ester 52 (94 mg, 0.20 mmole) is converted to the relativehydroxamic acid as described for compound 48b and eluted through flashsilica with EtOAc:MeOH (1:0 to 5:1) to give the title compound as awhite solid. ESI MS: m/z (rel intensity) 489.3 (M⁺+NH₄ ⁺, 55), 472.3(M⁺+H, 100).

a.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-N-(methane-sulfonyl)-propyl-aminopyrrolidine:The starting amine 44a (783 mg, 2.20 mmole) was converted to the titlecompound as described for 48a. ESI MS: m/z (rel intensity) 452 (M+NH₄⁺), 435 (M⁺+H, 75), 265 (100), 155 (75), 126 (40).

b.(1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-N-(methanesulfonyl)-propyl-aminopyrrolidineThe starting ester 53a (614 mg, 1.41 mmole) was converted to the titlecompound as described for 48b. ESI MS: m/z (rel intensity) 452.9 (M+NH₄⁺, 100), 435.8 (M⁺+H, 55).

Example 54

a.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-4-methoxyphenyl-sulfonylamino-pyrrolidine:The primary amine 42b (400 mg, 1.27 mmole) is converted to the titlecompound with p-methoxybenzenesulfonyl chloride (316 mg, 1.53 mmole) asdescribed for compound 485. CI⁺ MS: m/z (rel intensity) 502 (M⁺+NH₄ ⁺,12), 485 (M⁺+H, 10), 315 (100).

b.(1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-4-methoxyphenyl-sulfonylamino-pyrrolidine:The starting ester 54a (480 mg, 0.99 mmole) is converted to the relativehydroxamic acid as described for compound 48b and eluted through flashsilica with EtOAc:MeOH:HCO₂H (1:0:0 to 4:1:0.1) to give the titlecompound as a white solid which was recrystallized fromacetonitrile:water to give white crystalls. ESI MS: m/z (rel intensity)486 (M⁺+H, 100), 503 (M⁺+NH₄, 30).

Example 55

a.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-(-1-oxyhexyl)-aminopyrrolidine:The primary amine 42b (500 mg, 1.59 mmole) is converted to the titlecompound with hexanoyl chloride (268 μL, 1.91 mmole) as described forcompound 48a. ESI MS: m/z (rel intensity) 413.2 (M⁺+H, 70), 430.2(M⁺+NH₄, 100).

b.(1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-(-1-oxyhexyl)-aminopyrrolidine:The starting ester 55a (560 mg, 1.35 mmole) is converted to the relativehydroxamic acid as described for compound 48b and eluted through flashsilica with EtOAc:MeOH:HCO₂H (1:0:0 to 4:1:0.1) to give the titlecompound as a pale orange, viscous sap which would not solidify. ESI MS:m/z (rel intensity) 431.4 (M⁺+NH₄ ⁺, 25), 414.4 (M⁺+H, 35), 102 (100).

Example 56

a.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-p-biphenyl-aminopyrrolidine:The primary amine 42b (1.00 g, 3.19 mmole) is converted to the titlecompound with 4-biphenyl chloride (761 mg, 3.51 mmole) as described forcompound 48a. CI⁺ MS: m/z (rel intensity) 4.95 M⁺+H, 30), 325 (100), 198(55), 155 (27).

b.(1N)-4-Methoxyphenylsulfonyl-(2R)-hydroxycarboxamido-(4S)-p-biphenylylaminopyrrolidine:The starting ester 56a (200 mg, 0.404 mmole) is converted to therelative hydroxamic acid as described for compound 48b and elutedthrough flash silica with EtOAc:MeOH (1:0:0 to 9:1) to give 129 mg (65%)of the title compound. ESI MS: m/z (rel intensity) 496.0 (M⁺+H, 100),513.0 (M+NH₄ ⁺, 60), 517.8 (M-+Na, 15).

Example 57

a.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-methylcarboxamyl-aminopyrrolidine:The primary amine 42b (470 mg, 1.49 mmole) is taken in 4 mL of dioxanewith 1 mL of triethyl amine and a catalytic amount of DMAP and thentreated with methyl isocyanate (106 μL, 1.80 mmole) and stirred for 16hrs at rt. The mixture is then partitioned between EtOAc and 1N HCl andthe organic layer is washed with brine, dried over MgSO₄, filtered andevaparated. The residue is then chromatographed over flash silica withhexane:EtOAc (1:2 to 0:1) to give white solid. CI⁺ MS: m/z (relintensity) 389 (M⁺+NH₄ ⁺, 5), 372 (M⁺+H, 25), 202 (100).

b.(1N)-4-Methoxyphenylsulfonyl-(2R)-hydroxycarboxamido-(4S)-methyl-carboxamyl-aminopyrrolidine:The starting ester 57a (351 mg, 0.95 mmole) is converted to the relativehydroxamic acid as described for compound 48b and eluted through flashsilica with EtOAc:MeOH (8:1) to give the title compound as a white solidwhich was recrystallized from acetonitrile:water to give white crystals.ESI MS: m/z (rel intensity) 411.0 (M⁺+K, 30), 373.1 (M⁺+H, 100), 316(32).

Example 58

a.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-N-(1-oxo-2R-benzyloxy-propyl)-aminopyrrolidine:The starting amine 42b (465 mg, 1.48 mmole), and the startingL-o-benzyllactic acid (319 mg, 1.78 mmole) is taken in 4 mL of DMF inthe presence of 1.5 mL of N-methylmorpholine, EDAC (568 mg, 2.96 mmole)and HOBT (599 mg, 4.44 mmole). The resulting mixture is stirred at rtfor 16 hr and then partitioned between 1N HCl and EtOAc. The organiclayer is then washed 1× with dil NaHCO₃, 1× with brine, dried overMgSO₄, filtered and evaparated. The crude residue is thenchromatographed with hexane:EtOAc (2:1 to 1:3) to give the titlecompound. ESI MS: m/z (rel intensity) 477.2 (M⁺+H, 100), 494.2 (M⁺+NH₃,10).

b.(1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-N-(1-oxo-2R-benzyloxypropyl)-aminopyrrolidine:The staring methylester 58b (480 mg, 1.01 mmole) is taken in 2 mL ofmethanol, treated with NH₂OK (2.5 mL, 1.25 M in methanol, solutionprepared as descried in Fieser and Fieser, Vol 1, p 478) and stirredovernight. The following morning, dry silica (3 mL) is added to themixture and the solvent removed under vaccuum. The dry silica is pouredon the top of a flash silica gel column which is subsequently elutedwith EtOAc:MeOH (1:0 Ø 4:1) to give 338 mg (70%) of a white foamy solid.ESI MS: m/z (rel intensity) 478.3 (M⁺+H, 100), 500.2 (M⁺+Na, 12).

Example 59

a. 2R-benzyloxy-3-phenylproionic acid: Sodium hydride (2.9 g, 120mmole), is washed 2 times with hexane and covered with 50 mL of DMF. Thestarting L-3-phenyllactic acid (5 g, 30.1 mmole) is then added inportions and, after fizzing ceased, the mixture is heated to 55° C. for1 hr. The mixture is then cooled to 0° C. and benzyl bromide (4.3 mL,36.1 mmole) is added dropwise. The mixture is heated to 60° C. for 3 hrand then partitioned between hexane:EtOAc (1:1) and 1N HCl. The organiclayer is washed with brine, dried over MgSO₄, filtered and evaparated.The residue is chromatographed over flash silica with hexane:EtOAc (9:1to 0:1) to give a colorless oil. ESI MS: m/z (rel intensity) 274.3(M⁺+NH₃, 100).

b.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-N-(1-oxo-2R-benzyloxy-3-phenylpropyl)-aminopyrrolidine:The starting amine 44a (800 mg, 2.55 mmole), and the starting benzyllactic acid 59a (784 mg, 3.06 mmole) is taken in 5 mL of DMF in thepresence of 1 mL of N-methylmorpholine, EDAC (979 mg, 5.10 mmole) andHOBT (1.03 mg, 7.65 mmole). The resulting mixture is stirred at rt for16 hr and then partitioned between 1N HCl and EtOAc. The organic layeris then washed 1× with dil NaHCO₃, 1× with brine, dried over MgSO₄,filtered and evaparated. The crude residue is then chromatographed withhexane:EtOAc (8:1 to 1:1) to give the title compound. ESI MS: m/z (relintensity) 553.2 (M⁺+H, 100), 570.3 (M⁺+NH₃, 18).

c.(1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-N-(1-oxo-2R-benzyloxy-3-phenylpropyl)-aminopyrrolidine:The starting methylester 59b (700 mg, 127 mmole) is taken in 2 mL ofmethanol, treated with NH₂OK (2.5 mL, 1.25 M in methanol, solutionprepared as described in Fieser and Fieser, Vol 1, p 478) and stirredovernight. The following morning, dry silica (3 mL) is added to themixture and the solvent removed under vaccuum. The dry silica is pouredon the top of a flash silica gel column which is subsequently elutedwith hexane:EtOAc (1:1 Ø 0:1) to give a white foamy solid. ESI MS: m/z(rel intensity) 553.3 (M⁺+H, 100), 576.3 (M⁺+Na, 23).

Example 60

a.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-N-(1-oxo-2R-benzyloxy-propyl)-propyl-aminopyrrolidine:The starting amine 44a (636 mg, 1.79 mmole), and the startingL-o-benzyllactic acid (390 mg, 2.15 mmole) is taken in 5 mL of DMF inthe presence of 1 mL of N-methylmorpholine, EDAC (687 mg, 3.58 mmole)and HOBT (762 mg, 5.37 mmole). The resulting mixture is stirred at rtfor 16 hr and then partitioned between 1N Ha and EtOAc. The organiclayer is then washed 1× with dil NaHCO₃, 1× with brie dried over MgSO₄,filtered and evaparated. The crude residue is then chromatographed withhexane:EtOAc (8:1 to 1:1) to give the title compound. ESI MS: m/z (relintensity) 595.2 (M⁺+H, 100).

b.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-N-(1-oxo-2R-hydroxypropyl)-propyl-aminopyrrolidine:The starting ether 60a (700 mg, 1.35 mmole) is taken in 25 mL ofmethanol with catalytic 10% Pd—C and H₂SO₄ and hydrogenated for 3 hrs at54 psi in a Parr apparatus. The material is then filtered through a padof celite, evaparated to dryness and chromatographed over flash silicato give a clear gum. ESI MS: m/z (rel intensity) 429.3 (M⁺+H, 100),446.3 (M⁺+NH₃, 12).

c.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-N-(1-oxo-2R-hydroxypropyl)-propyl-aminopyrrolidine:The starting methylester 60b (331 mg, 0.771 mmole) is taken in 1 mL ofmethanol treated with NH₂OK (1.23 mL, 1.25 M in methanol, solutionprepared as described in Fieser and Fieser, Vol 1, p 478) and stirredovernight. The following morning, dry silica (3 mL) is added to themixture and the solvent removed under vaccuum. The dry silica is pouredon the top of a flash silica gel column which is subsequently elutedwith hexane:EtOAc (1:1 Ø 0:1) to give a white foamy solid. ESI MS: m/z(rel intensity) 519.3 (M⁺+H, 100), 536.3 (M⁺+NH₃, 60).

Example 61

a.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-N,N-(1-oxo-2R-benzyloxy-3-phenylpropyl)-propyl-aminopyrrolidine:The acid 59a (530 mg, 1.68 mmole) was taken in 15 mL of CH₂Cl₂ andtreated with oxalyl chloride (293 μL, 3.37 mmole). A catalytic drop ofDMF was added and the mixture was stirred for a total of 3.5 hrs andthen evaparated to dryness. The residue was taken in 15 mL of CH₂Cl₂ andadded to a solution of the starting amine 44a (449 mL, 126 mmole) in 10mL of CH₂Cl₂ and 2 mL of triethyl amine. The resulting solution wasstirred for 16 hrs. and then partitioned between EtOAc and 1 N HCl. Theorganic layer was washed 1 time with 1 N HCl, 2 times with NaHCO₃, 1time with brine, dried over MgSO₄, filtered and evaparated to give 740mg of crude gum. This is then chromatographed over flash silica withhexane:EtOAc (4:1 to 1:2) to give a pale yellow gum. ESI MS: m/z (relintensity) 595.2 (M⁺+H, 100).

b.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-N-(1-oxo-2R-hydroxy-3-phenylpropyl)-propyl-aminopyrrolidine:The starting ether 61a (480 mg, 0.807 mmole) is taken in 20 mL ofmethanol with catalytic 10% Pd—C and H₂SO₄ and hydrogenated for 16 hrsat 50 psi in a Parr apparatus. The material is then filtered through apad of celite, evaparated to dryness and chromatographed over flashsilica with EtOAc to give a clear gum. ESI MS: m/z (rel intensity) 505.3(M⁺+H, 100), 522.3 (M⁺+NH₃, 15).

c.(1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-N-(1-oxo-2R-hydroxy-3-phenylpropyl)-propyl-aminopyrrolidine:The starting methylester 61b (307 mg, 0.608 mmole) is taken in 1 mL ofmethanol, treated with NH₂OK (1.23 mL, 1.25 M in methanol, solutionprepared as described in Fieser and Fieser, Vol 1, p 478) and stirredovernight. The following morning, dry silica (3 mL) is added to themixture and the solvent removed under vaccuum. The dry silica is pouredon the top of a flash silica gel column which is subsequently elutedwith hexane:EtOAc (1:1 Ø 0:1) to give a white foamy solid. ESI MS: m/z(rel intensity) 506.3 (M⁺+H, 100), 526.3 (M⁺+Na, 12).

Examples 62-63

In the following examples W and Z are hydrogen, and Y is OH, n is 1, Aris substituted or unsubstituted phenyl and X and Q refer to substituentson the phenyl ring:

Example X Y 62 OMe CH₂ 63 OnBu CH₂ 64 OMe O 65 OnBu O 66 OMe SO₂ 67 OnBuSO₂

Example 62

a.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-1-piperidyl-pyrrolidine:The starting amine 42b (1.00 g, 3.19 mmole) is dissolved in 10 mL ofmethanol and stirred for 16 hrs in the presence of glutonic dialdehyde(961 mg, 50 wt % in water, 4.8 mmole), sodium cyanoborohydride (503 mg,8 mmole), sodium acetate (1 g) and 1 mL of acetic acid. The mixture isevaparated to dryness and then partitioned between dil. NaHCO₃ and EtOAcand the organic layer is washed 2 times with NaHCO₃, 1 time with brine,dried over MgSO₄, filtered and evaparated to give a clear colorlessglass which is chromatographed over flash silica with hexane:EtOAc (4:1to 1:1) to give the desired product as a clear glass. ESI MS: m/z (relintensity) 383 (M⁺+H, 100), 211 (38).

b.(1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-1-piperidyl-pyrrolidine:The starting methylester 62a (1.00 g, 2.62 mmole) is taken in 3 mL ofmethanol, treated with NH₂OK (4 mL, 1.25 M in methanol, solutionprepared as described in Fieser and Fieser, Vol 1, p 478) and stirredovernight. The following morning, dry silica (4 mL) is added to themixture and the solvent removed under vaccuum. The dry silica is pouredon the top of a flash silica gel column which is subsequently elutedwith EtOAc MeOH (1:0 Ø 4:1) to give a pale orange solid. ESI MS: m/z(rel intensity) 384 (M⁺+H, 100), 406 (M⁺+Na, 82), 422 (M⁺+K, 65).

Example 63

a.(1N)-4-n-Butoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-1-piperidyl-pyrrolidine:The starting amine 43c (1.06 g, 1.88 mmole) is taken in 10 mL of DMF and1.5 mL of NEt₃ and treated with 2 mL of 2-bromoethyl ether. Theresulting mixture is then heated to 60° C. for 16 hr and partitionedbetween dil Na₂CO₃ and EtOAc. The organic layer is then dried overMgSO₄, filtered and evaparated. The crude residue was chromatographedover flash silica with Hexane:EtoAc (1:1 to 0:1) to give the titlecompound as a clear oil. ESI MS: m/z (rel intensity) 425 (M⁺+H).

b.(1N)-4-n-Butoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-piperidyl-pyrrolidine:The starting methylester 63a (851 mg, 2.01 mmole) is taken in 1 mL ofmethanol, treated with NH₂OK (0.381 mL, 0.86 M in methanol, solutionprepared as described in Fieser and Fieser, Vol 1, p 478) and stirredovernight. The following morning, dry silica (2 mL) is added to themixture and the solvent removed under vaccuum. The dry silica is pouredon the top of a flash silica gel column which is subsequently elutedwith EtOAc:MeOH (1:0 Ø 9:1) to give 543 mg (64%) of a pale orange solid.This was recrystallized from hexane:EtOAc to give pale orange solid. ESIMS: m/z (rel intensity) 426.1 (M⁺+H).

Example 64

a.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-morpholinopyrrolidine:The starting anine 42b (590 mg, 1.88 mmole) is taken in 4 mL of DMF and1 mL of NEt₃ and treated with 1 mL of 2-bromoethyl ether. The resultingmixture is then heated to 60° C. for 3 hr and partitioned between dilNaCO₃ and EtOAc. The organic layer is then dried over MgSO₄, filteredand evaparated. The crude residue was chromatographed over flash silicawith EtOAc:MeOH (9:1) to give the title compound as a white solid. ESIMS: m/z (rel intensity) 385.1 (M+H).

b.(1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-morpholinopyrrolidine:The starting methylester 64a (310 mg, 0.86 mmole) is treated with NH₂OK(2 mL, 1.25 M in methanol) in 4 mL mL of methanol as described for 63bto give material which is puffed to a white solid under vacuum and notrecrystallized. ESI MS: m/z (rel intensity) 386.1 (M⁺+H, 100), 565.1(12), 424.0 (15), 408.1 (M+NH₄ ⁻, 7), 218.1 (20), 202.1 (13).

Example 65

a.(1N)-4-n-Butoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-morpholinopyrrolidine:The starting amine 43c (7.2 g, 20.2 mmole), was taken in 50 mL of DMFand 15 mL of Et₃N with 2-bromoethyl ether and converted to the titlecompound as described for compound 63a. ESI MS: m/z (rel intensity)427.18 (M⁺+H).

b.(1N)-4-n-Butoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-morpholino-pyrrolidine:The starting methylester 65a (6.5 g, 15.2 mmole) is treated with NH₂OK(24 mL, 1.25 M in methanol) in 20 mL mL of methanol as described for 63bto give material which is puffed to a white solid under vacuum and notrecrystallized. ESI MS: m/z (rel intensity) 428.08 (M⁺+H, 100), 450.07(M⁺+Na, 8), 465.99 (M⁺+K, 15).

Example 66

a.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-(4,4-dioxythio-morpholino)-pyrrolidine:The starting amine 42b (560 mg, 1.79 mmole), was taken in 10 mL of DMFand 1 mL of N-methylmorpholine with di-2-bromoethylsulfone (500 mg, 1.79mmole) and converted to the title compound as described for compound63a. ESI MS: m/z (rel intensity) 433.1 (M⁺+H).

b.(1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-(4,4-dioxy-thiomorpholino)-pyrrolidine:The starting methyl ester 66a (420 mg, 976 mmole), was converted to thetitle compound as described for compound 63b. This material was thenrecrystallized from EtOAC:methanol to give first crop crystalls andsecond crop als. ESI MS: m/z (rel intensity) 434.0 (M⁺+H, 100), 456.0(M⁺+Na, 32).

Example 67

a.(1N)-4-n-Butoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-(4,4-dioxythio-morpholino)-pyrrolidine:The starting amine 43c (1.00 g, 2.81 mmole), was taken in 5 mL of DMFand 2 mL of N-methylmorpholine with di-2-bromoethylsulfone (750 mg, 2.68mmole) and converted to the title compound as described for compound63a. ESI MS: m/z (rel intensity) 475.0 (M⁺+H).

b.(1N)-4-n-Butoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-(4,4-dioxythiomorpholino)-pyrrolidine:The starting methylester 67a (1.01 g, 2.83 mmole) is treated with NH₂OK(4 ml, 1.25 M in methalol) in 4 mL of methanol as described for 63b togive material which is puffed to a white solid under vacuum and notrecrystallized. ESI MS: m/z (rel intensity) 476.1 (M⁺+H, 100), 498.1(M⁺+Na, 22).

Example X Q R P 68 OMe Me H H 69 OnBu Me H H 70 OMe CH₂CH═CH₃ H H 71OnBu H CH₃ CH₃ 72 OnBu H H CH₃ 73 O(CH₂)₂OMe CH₃ H H 74 OPh CH₃ H H 75OCH(CH₃)₂ CH₃ H H

Example 68

a.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-1N-(3N-methylhydantoyl)-pyrrolidine:Diethylazodicarboxylate (1.8 mL, 11.42 mmole) is added to a stirredsolution of the starting alcohol 1a (3.0 g, 9.51 mmole),triphenylphosphene (3.74 g, 9.51 mmole), and 1-methylhydantoin (1.3 g,11.42 mmole) in 30 mL of CH₂Cl₂ and stirred for 16 hrs at rt. Themixture is then chromatographed over flash silica with hexane and thenhexane:EtOAc (1:1) to give colorless glass which is recrystallized frommethanol to give a white powder. ESI MS: m/z (rel intensity) 412.1(M⁺+H, 100), 429.1 (M⁺+NH₃, 45).

b.(1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-1N-(3N-methylhydantoyl)-pyrrolidine:The starting methyl ester 68a (500 mg, 1.22 mmole) is taken in 7 mL ofmethanol/tetrahydrofuran (1:1), and treated with NH₂OK (2.5 ml, 1.25M inmethanol) and stirred overnight. The following morning, dry silica (1.5mL) is added to the mixture and the solvent removed under vacuum. Thedry silica is poured on top of a flash silica column which issubsequently eluted with ethyl acetate followed with ethyl acetate (9:1)to give a clear glass which is puffed to a foamy solid by slight heatingunder vacuum. The product is recrystallized from cold methanol to give awhite powder. ESI MS: m/z (rel intensity) 413.0 (M⁺+H, 100),430.0(M⁺+NH₃, 55).

Example 69

a.(1N)-n-Butoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-1-(3N-methyl-hydantoyl)-pyrrolidine:Diethylazodicarboxylate (1.6 mL, 10.24 mmole) is added to a stirredsolution of the starting alcohol 29a (3.05 g, 8.53 mmole),triphenylphosphine (3.36 g, 12.80 mmole), and 1-methyl-hydantoin (1.17mg, 10.24 mmole) in 60 mL of CH₂Cl₂ and stirred for 16 hrs at rt. Themixture is then chromatographed over silica with hexane followed byhexane:EtOAc (1:1) and finally with EtOAc to give a colorless gum. Theproduct was recrystallized from EtOAc-hexane to give a white powder. ESIMS: m/z (rel intensity) 454.05 (M⁺+H, 100), 471.05 (M⁻+NH₃, 30).

b.(1N)-4-n-butoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-N-(3N-methylhydantoyl)-pyrrolidine:The starting methyl ester 69a (500 mg, 1.22 mmole) is taken in 7 mL ofmethanol/tetrahydrofuran (1:1), and treated with NH₂OK (2.5 ml, 1.25 Min methanol) and stirred overnight. The following morning, dry silica(1.5 ml) is added to the mixture and the solvent removed under vacuum.The dry silica is poured on top of a flash silica column which issubsequently eluted with ethyl acetate followed with ethylacetate:methanol (9:1) to give a clear glass which is puffed to a foamysolid by slight heating under vacuum. The product is recrystallized fromcold methanol to give a white powder. ESI MS: m/z (rel intensity) 455.0(M⁺+H, 100), 472.0 (M⁺+NH₃, 50).

Example 70

a.(1N)-4-n-butoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-1N-(3N-allylhydantol)-pyrrolidine:Diethylazodicarboxylate (1.1 mL, 6.98 mmole) is added to a stirredsolution of the starting alcohol 1a (2.08 g, 5.82 mmole),triphenylphosphine (2.29 g, 8.73 mmole), and 1-allylhydantoin (979 mg,6.98 mmole) in 40 mL of CH₂Cl₂ and stirred for 16 hrs at rt. The mixtureis then chromatographed over silica with hexane:EtOAc (8:2) followed byhexane:EtOAc (1:1) to give a colorless gum. ESI MS: m/z (rel intensity)480.0 (M⁺+H, 100), 497.0(M⁺+NH₃, 20).

b.(1N)-4-n-butoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-1N-(3N-allyl-hydantoyl)-pyrrolidine:The staring methyl ester 70a (549 mg, 1.15 mmole) is taken in 2 mL ofmethanol/tetrahydrofuran (1:1), and treated with NH₂OK (1.5 ml, 125 M inmethanol) and stirred overnight. The following morning, dry silica (1.5mL) is added to the mixture and the solvent removed under vacuum. Thedry silica is poured on top of a flash silica column which issubsequently eluted with ethyl acetate followed with ethylacetate:methanol (8:2) to give a clear glass which is purified to afoamy solid by slight heating under vacuum. The product was resized fromcold methanol to give a of white powder. ESI MS: m/z (rel intensity)481.2 (M⁺+H, 100), 498.2(M⁺+NH₃, 60).

Example 71

a.(1N)-4-n-butoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-1N-(4-dimethylhydantoyl)-pyrrolidine:Diethylazodicarboxylate (0.530 ml, 3.36 mmole) is added to a stirredsolution of the starting alcohol 29a (1.00 g, 2.80 mmole),triphenylphosphine (1.10 g, 4.20 mmole), and 5,5-dimethylhydantoin (430mg, 3.36 mmole) in 20 mL of CH₂Cl₂ and stirred for 16 hrs at rt. Themixture is then chromatographed over silica with hexane:EtOAc (8:2)followed by hexane:EtOAc (1:1) to give a colorless gum. ESI MS: m/z (relintensity) 468.1 (M⁺+H, 100), 485.1(M⁺+NH₃, 30).

b.(1N)-4-n-butoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-1N-(4-dimethylhydantoyl)-pyrrolidine:The starting methyl ester 71a (754 mg, 1.61 mmole) is taken in 2 mL ofmethanol/tetrahydrofuran (1:1), and treated with NH₂OK (2.0 mL, 1.25M inmethanol) and stirred overnight. The following morning, dry silica (1.5mL) is added to the mixture and the solvent removed under vacuum. Thedry silica is poured on top of a flash silica column which issubsequently eluted with hexane:ethyl acetate (1:1) followed withhexane:ethyl acetate (2:8) and finally with ethyl acetate:methanol (8:2)to give a clear glass which is puffed to a foamy solid by slight heatingunder vacuum. The product is recrystallized from cold methanol to givethe title compound as a white powder. ESI MS: m/z (rel intensity) 469.0(M⁺+H, 100), 486.0 (M⁺+NH₃, 10).

Example 72

a.(1N)-4-n-butoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-1N-(4S-methyl-hydantoyl)-pyrrolidine:Diethylazodicarboxylate (0.530 mL, 3.36 mmole) is added to a stirredsolution of the starting alcohol 29a (1.00 g, 2.80 mmole),triphenylphosphine (1.10 g, 4.20 mmole), and (L)₅-methylhydantoin (383mg, 3.36 mmole) in 20 mL of CH₂Cl₂ and stifled for 16 hrs at rt. Themixture is then chromatographed over silica with hexane:EtOAc (8:2)followed by hexane:EtOAc (1:1) to give a colorless gum. This is thenrepurified over a second column eluting first with hexane:EtAcO (1:1)followed by EtOAc:hexane (8:2). ¹H NMR showes a mitsunobu impurity (20%)remaining after two column purifications and the material is carriedforwared to the next step without further purification. ESI MS: m/z (relintensity) 454.0 (M⁺+H, 100), 471.0 (M⁺+NH₃, 20).

b.(1N)-4-n-butoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-1N-(4S-methylhydantoyl)-pyrrolidine:The starting methyl ester 72a (497 mg, 1.10 mmole) is taken in 2 mL ofmethanol/tetrahydrofuran (1:1), and treated with NH₂OK (1.5 mL, 1.25M inmethanol) and stirred overnight. The following morning, dry silica (1.5mL) is added to the mixture and the solvent removed under vacuum. Thedry silica is poured on top of a flash silica column which issubsequently eluted with ethyl acetate followed with ethylacetate:methanol (9:1) to give a clear glass which is puffed to a foamysolid by slight heating under vacuum. The product is recrystallized fromcold methanol to give the title compound as a of white powder. ESI MS:m/z (rel intensity) 455.0 (M⁺+H, 100), 472.0 (M⁺+NH₃, 30).

Example 73

a.(1N)-4-(2-methoxyethoxy)-phenylsulfonyl-(2R)-carbomethoxy-(4S)-1N-(3N-methylhydantoyl)-pyrrolidine:Diethylazodicarboxylate (0.546 mL, 3.47 mmole) is added to a stirredsolution of the starting alcohol 34b (1.04 g, 2.89 mmole),triphenylphosphine (1.14 g, 4.34 mmole), and 1-methylhydantoin (396 mg,3.47 mmole) in 20 mL of CH₂Cl₂ and stirred for 16 hrs at rt. The mixtureis then chromatographed over silica with hexane:EtOAc (1:1) followed byhexane:EtOAc (2:8) to give a colorless gum ESI MS: m/z (rel intensity)456.14 (M⁺+H, 100), 473.15 (M⁺+NH₃, 10).

b.(1N)-4-(2-methoxyethoxy)-phenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-1N-(3N-methylhydantoyl)-pyrrolidine:The starting methyl ester 73a (725 mg, 1.59 mmole) is taken in 2 mL ofmethanol/tetrahydrofuran (1:1), and treated with NH₂OK (2 mL, 1.25 M inmethanol) and stirred overnight. The following morning, dry silica (1.5mL) is added to the mixture and the solvent removed under vacuum. Thedry silica is poured on top of a flash silica column which issubsequently eluted with ethyl acetate followed with ethylacetate:methanol (8:2) to give a clear glass which is purified to afoamy solid by slight heating under vacuum. The product wasrecrystallized from cold methanol to give the title compound as a whitepowder. ESI MS: m/z (rel intensity) 457.08 (M⁺+H, 100), 474.09 (M⁺+NH₃,60).

Example 74

a.(1N)-4-phenoxyphenylsulfonyl-(2R)-carbomethoxy-(4S)-1N-(3N-methylhydantoyl)-pyrrolidine:Diethylazodicarboxylate (0.570 mL, 3.62 mmole) is added to a stirredsolution of the starting alcohol 35b (1.14 g, 3.02 mmole),triphenylphosphine (1.19 g, 4.53 mmole), and 1-methyl-hydantoin (413 mg,3.62 mmole) in 20 mL of CH₂Cl₂ and stirred for 16 hrs at rt. The mixtureis then chromatographed over silica with hexane:EtOAc (8:2) followed byhexane:EtOAc (1:1) with product eluting with Hexane:EtOAc (2:8) to givea colorless gum ESI MS: m/z (rel intensity) 474.03 (M⁺+H, 100), 491.03(M⁺+NH₃, 20).

b.(1N)-4-phenoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-(4S)-1N-(3N-methylhydantoyl)-pyrrolidine:The starting methyl ester (1.50 g, 1.59 mmole) is taken in 10 mL ofmethanol/tetrahydrofuran (1:1), and treated with NH₂OK (5 mL, 1.25M inmethanol) and stirred overnight. The following morning, dry silica (5mL) is added to the mixture and the solvent removed under vacuum. Thedry silica is poured on top of a flak silica column which issubsequently eluted with ethyl acetate:hexane (1:1), then ethyl acetatefollowed with ethyl acetate:methanol (8:2) to give a clear glass whichis puffed to a foamy solid by slight heating under vacuum. The productis recrystallized from cold methanol to give the title compound as awhite powder. ESI MS: m/z (rel intensity) 475.09 (M⁺+H, 100), 497.07(M⁺+NH₃, 60).

Example 75

a. (±)-(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-5-pyrrolidinone:The 2-carboxy-β-lactam starting material (10 g, 77.5 mmoles) isdissolved in 200 ml of methanol at 0° C. followed by the addition of0.76M diazomethane until the color of the reaction mixture remainedyellow. The reaction is then stirred for an additional 30 minutes. Thisis evaporated down to get rid of excess methanol and diazomethane. Theyield is quantitative and the product is carried forward without furtherpurification.

The methyl ester produced above (11.08 g, 77.5 mmoles) is dissolved in500 mL of dry THF at 0° C. followed by the one portion addition oft-butoxide (9.15 g, 77.5 mmoles) and stirred for 1 hour. Next,4-methoxybenzene sulfonyl chloride (19.2 g, 93.0 mmoles) is added andthis stirred over night. The reaction is quenched with saturated sodiumbicarbonate until basic and extracted with ether 3 times. The etherlayer is washed with 1N HCl sodium bicarbonate, and ammonium chloride,dried over magnesium sulfate and evaporated done. Chromotography isperformed on silica gel using a solvent system of ethyl acetate:hexane(1:1) to give the title compound. CI⁺ MS: m/z (rel intensity) 314.0(M⁺+H, 100).

b. (±)-(1N)-4-Methoxyphenylsulfonyl-(2R)-carboxyl-5-pyrrolidinone:

The sulfonated methyl ester 75a (8.5 g, 27.12 mmoles) is dissolved in 60mL of a THF and methanol (3:1). Lithium hydroxide (2.27 g, 94.9 mmoles)is then added in THF and methanol (3:1). An additional 10 ml of methanolis added to the reaction mixture to improve solubility. The reactionstirred for 3 hours. The reaction is quenched with water and thenevaporated down to get rid of the organic solvents. The water layer isextracted one time with ether. Then the water layer is acidified to pH=2and this is extracted with ethyl acetate 3 times and washed with sodiumchloride and dried over magnesium sulfate. This is evaporated down togive give the title compound. CI⁺ MS: m/z (rel intensity) 300.0(M⁺+100).

c.(±)-(1N)-Methoxyphenylsulfonyl-(2R)-O-benzyl-N-hydroxycarboxamido-5-pyrrolidinone:

The carboxylic acid 75b (1.0 g, 3.3 mmoles) is dissolved in 15 mL of DMFat 0 C followed by the addition of triethyl amine (1.37 mL, 9.9 mmoles),4-methylmorpholine N-oxide (1.08 g, 9.9 mmoles) 1-hydroxy-benzotriazole(1.33 g, 9.9 mmoles), and 1-ethyl-3(3-dimethyl-aminopropyl)carbodiimide(0.76 g, 4.01 mmoles). This stirred for 30 minutes followed by theaddition of the benzylamine (0.64 g, 4.01 mmoles). The reaction stirredovernight. The reaction is quencehed with saturated sodium bicarbonateand then extracted with ethyl acetate 3 times, washed with 1N HCl andsodium chloride, dried over magnesium sulfate and evaporated down.Chromotography is run on silica gel using ethyl acetate and methylenechloride (5:1) to give give the title compound. CI⁺ MS: m/z (relintensity) 404.0 (M⁺+H, 100).

d.(±)-(1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-5-pyrrolidinone:The benzyl protected lactam 75c (0.42 g, 1.04 mmoles) is dissolved in 20mL of ethyl acetate followed by the addition of palladium on activatedcarbon (wet) (0.042 g, [10% of weight]). The reaction flask is degassedof all oxygen and then put under hydrogen balloon pressure forovernight. After the flask is degassed of hydrogen, the palladium isfiltered off through celite and the ethyl acetate is rotovapped off. Thecompound is recrystallized with ethyl acetate and hexane to give thetitle compound. ESI MS: m/z (rel intensity) 314.0 (M⁺+H, 100).

Example 76

a.(1N)-4-Methoxyphenylsulfonyl-(2R)-carbomethoxy-4,4-dithiolethyl-pyrrolidine:The ketone 25a (1.5 g, 4.79 mmol) is dissolved in 30 mL of anhydrousdichloromethane and then ethanethiol (0.53 mL, 7.18 mmol) and boranetrifluoride etherate (0.24 mL, 1.91 mmol) is added. The resultingmixture is stirred at room temperature for 14 h. The reaction mixture isquenched by the the addition of 1N sodium hydroxide and then extracted 3times with ethyl acetate. The organic layers are washed with water andsaturated ammonium chloride solution, dried (MgSO₄), filtered andconcentrated under reduced pressure to give the title compound. CI⁺ MS:m/z 420 (M⁺+H)).

b.(1N)-4-Methoxyphenylsulfonyl-(2R)-N-hydroxycarboxamido-4,4-dithiolethylpyrrolidine:The thioketal 76a (0.32 g, 0.89 mmol) is added to a 1.5 M solution ofpotassium hydroxylamine solution (4.0 mL, prepared as described inFieser and Fieser, Vol. 1, p. 478.). The reaction mixture is stirredovernight and then acidified with 1N HCl. The resulting mixture is thenextracted 3 times with ethyl acetate, dried (MgSO₄), filtered andconcentrated under reduced pressure. Chromotography was performed onsilica gel using EtOAc:hexane:formic acid (1:1:0.1) as the eluent togive the title compound. ESI MS: m/z 421 (M⁺+H), 443 (M⁺+Na).

Examples 77-180

The following compounds are made using the methods described andexemplified above. In these Examples R₁ is HONH, Z and W are hydrogen,and Y and Ar substitution, as well as ring size are described in thechart below. Hence, a simplified diagram of the molecule exemplified is:

Y Ar n Example 78 —OH 4-NO₂—C₆H₄— 1 Example 79 —OH 4-i-BuO—C₆H₄— 1Example 80 —OH 4-(C₆H₅)O—C₆H₄— 1 Example 81 —OH 4-(4-F—C₆H₄)O—C₆H₄— 1Example 82 —OH 4-(4-Cl—C₆H₄)O—C₆H₄— 1 Example 83 —OH4-(4-Br—C₆H₄)O—C₆H₄— 1 Example 84 —OH 4-(4-Me—C₆H₄)O—C₆H₄— 1 Example 85—OH 4-(4-MeO—C₆H₄)O—C₆H₄— 1 Example 86 —OH 4-(4-CN—C₆H₄)O—C₆H₄— 1Example 87 —OH 4-(4-Me₂N—C₆H₄)O—C₆H₄— 1 Example 88 —OH 4-EtO—C₆H₄— 1Example 89 —OH 4-i-PrO—C₆H₄— 1 Example 90 —OH 4-n-PrO—C₆H₄— 1 Example 91—OH 4-Br—C₆H₄— 1 Example 92 —OH 4-C₆H₅—C₆H₄— 1 Example 93 —OH4-(4-F—C₆H₅)—C₆H₄— 1 Example 94 —OH 4-(4-Cl—C₆H₅)—C₆H₄— 1 Example 95 —OH4-(4-Br—C₆H₅)—C₆H₄— 1 Example 96 —OH 4-(4-Me₂N—C₆H₄)—C₆H₄— 1 Example 97—OH 4-(4-CN—C₆H₄)—C₆H₄— 1 Example 98 —OH 4-(4-MeO—C₆H₄)—C₆H₄— 1 Example99 —OH 4-(4-C₅H₄N)O—C₆H₄— 1 Example 100 —OH 4-(3-C₅H₄N)O—C₆H₄— 1 Example101 —OH 4-(2-C₅H₄N)O—C₆H₄— 1 Example 102 —OH C₆H₅CH₂CH₂— 1 Example 103—OH C₆H₅CH₂— 1 Example 104 —OH (4-C₅H₄N)CH₂CH₂— 1 Example 105 —OH(2-C₅H₄N)CH₂CH₂— 1 Example 106 —OH 4-(C₆H₁₁)O—C₆H₄— 1 Example 107 —OH4-(C₅H₁₁)O—C₆H₄— 1 Example 108 —OH 4-(C₆H₁₃)O—C₆H₄— 1 Example 109 —OH4-(CH₃OCH₂CH₂)O—C₆H₄— 1 Example 110 —OH 5-(2-pyridinyl)-2-thienyl- 1Example 111 —OH 5-(3-isoxazolyl)-2-thienyl- 1 Example 112 —OH5-(2-(methylthio)pyrimidin-4- 1 yl)-2-thienyl- Example 113 —OH5-(3-(1-methyl-5- 1 (trifluoromethyl)pyrazolyl)-2- thienyl- Example 114—NHP(O)(CH₃)C₆H₅ CH₃CH₂CH₂OC₆H₄— 1 Example 115 —NHCOCH₂C₆H₅CH₃CH₂CH₂OC₆H₄— 1 Example 116 —NHCO(2-pyridyl) CH₃CH₂CH₂OC₆H₄— 1 Example117 —NHCOCH₂NMe₂ CH₃CH₂CH₂OC₆H₄— 1 Example 118—NHCO-2-(1-methyl)-imidazyl CH₃CH₂CH₂OC₆H₄— 1 Example 119 —NHSO₂CH₃4-(4-C₅H₄N)O—C₆H₄— 1 Example 120 —NHCOC₆H₅ CH₃CH₂CH₂OC₆H₄— 1 Example 121—NMe₂ CH₃CH₂CH₂OC₆H₄— 1 Example 122 —N(CH₂CH₃)₂ CH₃CH₂CH₂OC₆H₄— 1Example 123 —NMe₂ 4-(4-C₅H₄N)O—C₆H₄— 1 Example 124 —N(CH₂CH₃)₂4-(4-C₅H₄N)O—C₆H₄— 1 Example 125 —N(CH₂CH₃)SO₂CH₃ CH₃CH₂CH₂OC₆H₄— 1Example 126 —N(CH₂CH₃)COCH₃ CH₃CH₂CH₂OC₆H₄— 1 Example 127—N(CH₂CH₃)SO₂CH₃ 4-(4-C₅H₄N)O—C₆H₄— 1 Example 128 —N(CH₂CH₃)COCH₃4-(4-C₅H₄N)O—C₆H₄— 1 Example 129 —N(CH₃)CO(2-pyridyl) CH₃CH₂CH₂OC₆H₄— 1Example 130 —N(CH₃)CO(4-pyridyl) CH₃CH₂CH₂OC₆H₄— 1 Example 131—N(CH₃)COC₆H₅ CH₃CH₂CH₂OC₆H₄— 1 Example 132—N(CH₃)CO-1N-methylpiperazine CH₃CH₂CH₂OC₆H₄— 1 Example 133 —N(CH₃)COHCH₃CH₂CH₂OC₆H₄— 1 Example 134 —N(CH₃)COCH₂OCH₃ CH₃CH₂CH₂OC₆H₄— 1 Example135 —N(CH₃)COCH(CH₃)₂ CH₃CH₂CH₂OC₆H₄— 1 Example 136 —N(CH₃)CO(furanyl)CH₃CH₂CH₂OC₆H₄— 1 Example 137 —N(CH₃)CO(oxazolinyl) CH₃CH₂CH₂OC₆H₄— 1Example 138 —N(CH₃)COCH₂CN CH₃CH₂CH₂OC₆H₄— 1 Example 139—N(CH₃)CO(CH₂)N(CH₃)₂ CH₃CH₂CH₂OC₆H₄— 1 Example 140—N(CH₃)SO₂-3-(1N-methylimidazyl) CH₃CH₂CH₂OC₆H₄— 1 Example 141—N(CH₃)SO₂CH(CH₃)₂ CH₃CH₂CH₂OC₆H₄— 1 Example 142 —CH₂NHSO₂CH₃ CH₃OC₆H₄—1 Example 143 —CH₂NHSO₂C₆H₅ CH₃OC₆H₄— 1 Example 144 —CH₂NHCOC₆H₅CH₃OC₆H₄— 1 Example 145 —CH₂NHCOCH₂CH₂CH₃ CH₃OC₆H₄— 1 Example 146—CH₂N(CH₃)COCH₃ CH₃OC₆H₄— 1 Example 147 —CH₂N(CH₃)SO₂C₆H₅OMe CH₃OC₆H₄— 1Example 148 —CH₂N(CH₂C₆H₅)SO₂CH₃ CH₃OC₆H₄— 1 Example 149 —OH CH₃OC₆H₄— 2Example 150 —S-C₆H₅ CH₃OC₆H₄— 2 Example 151 —(OMe)₂ CH₃OC₆H₄— 2 Example152 —OH BrC₆H₄— 2 Example 153 -3-methyl-1-hydantoyl- 4-EtO—C₆H₄— 1Example 154 -3-methyl-1-hydantoyl- 4-i-PrO—C₆H₄— 1 Example 155-3-methyl-1-hydantoyl- 5-(2-pyridinyl)-2-thienyl- 1 Example 156-3-methyl-1-hydantoyl- 4-Br—C₆H₄— 1 Example 157 -3-methyl-1-hydantoyl-2-Me-4-Br—C₆H₄— 1 Example 158 -3-methyl-1-hydantoyl- 4-(C₆H₄)O—C₆H₄— 1Example 159 -3-methyl-1-hydantoyl- 4-(4-F—C₆H₄)O—C₆H₄— 1 Example 160-3-methyl-1-hydantoyl- (4-C₅H₄N)CH₂CH₂— 1 Example 161-3-methyl-1-hydantoyl- 4-(4-C₅H₄N)O—C₆H₄— 1 Example 162 -1N-morpholino4-EtO—C₆H₄— 1 Example 163 -1N-morpholino 4-i-PrO—C₆H₄— 1 Example 164-1N-morpholino 5-(2-pyridinyl)-2-thienyl- 1 Example 165 -1N-morpholino4-Br—C₆H₄— 1 Example 166 -1N-morpholino 2-Me-4-Br—C₆H₄— 1 Example 167-1N-morpholino 4-(C₆H₅)O—C₆H₄— 1 Example 168 -1N-morpholino4-(4-F-C₆H₄)O—C₆H₄— 1 Example 169 -1N-morpholino (4-C₅H₄N)CH₂CH₂— 1Example 170 -1N-morpholino 4-(4-C₅H₄N)O—C₆H₄— 1 Example 171-1N-valerolactamyl- (4-C₅H₄N)OC₆H₄— 1 Example 172 -1N-valerolactamyl-4-n-BuOC₆H₄— 1 Example 173 —(OMe)₂ CH₃CH₂OC₆H₄— 1 Example 174 —(OMe)₂CH₃CN₂CH₂OC₆H₄— 1 Example 175 —(OMe)₂ 4-(4-C₅H₄N)O-C₆H₄— 1 Example 176—(OCH₂CH₃)₂ CH₃CH₂OC₆H₄— 1 Example 177 —(OCH₂CH₃)₂ CH₃CN₂CH₂OC₆H₄— 1Example 178 —(OCH₂CH₃)₂ 4-(4-C₅H₄N)O—C₆H₄— 1 Example 179 —(OCH₂CH₂OCH₃)CH₃CH₂OC₆H₄— 1 Example 180 —(OCH₂CH₂OCH₃) CH₃CN₂CH₂OC₆H₄— 1 Example 181—(OCH₂CH₂OCH₃) 4-(4-C₅H₄N)O-C₆H₄— 1

Examples 78-113 are prepared analogously to Example 1 using theappropriately functionalized sulfonyl chloride. The sulfonyl chlorideswhich are used to prepare the above examples are either purchased fromcommericial sources or prepared via known methods. For example, the4-phenoxyphenylsulfonyl chloride used for the preparation of Example 17,was prepared as descried by R. J. Cremlyn et al in Aust. J. Chem., 1979,32, 445.52.

Examples 114-120 are prepared using methods described in examples 42-61using the appropriate alkyl, acyl, sulfonyl, phosphinyl or isocyanatederivative.

Examples 129-141 are prepared by first mono-methylating the appropriateprimary amine derivative as described by S. Krishnamurthy et al inTetrahedron Lett. 1983, 23 (33), 3315, and then adding to adding theappropriate alkyl acyl sulfonyl, phosphinyl or isocyanate derivative asdescribed in examples 42-61.

Examples 142-148 are prepared from cyanide addition into mesylate 15afollowed by reduction to the corresponding free amine and treatment withthe appropriate alkyl acyl, sulfonyl, or phosphinyl derivative.

Examples 149-152 are prepared by ketalization or reduction and/ornucleophillic substitution of the appropriately functionalized4-ketopipecolic acid described by J.-P. Obrecht et al in OrganicSynthesis 1992, 200.

Examples 153-161 are prepared as described for example 68.

Examples 162-170 are prepared as described for example 65.

Examples 171-172 are prepared by acylation of a primary amine of type43c with 5-bromovaleryl chloride followed base promoted ring closure andhydroxamic acid formation.

Examples 173-181 are prepared by standard ketalization methods ofketones of type 25a.

These examples provide the skilled artisan with sufficient guidance asto making the present invention and do not limit it in any way.

Composition and Method of Use Examples

The compounds of the invention are useful to prepare composition for thetreatment of ailments and the like. The following composition and methodexamples do not limit the invention but provide guidance to the skilledartisan to prepare and use the compounds, compositions and methods ofthe invention. In each case the compounds formula I may be substitutedfor the example compound shown below with similar results.

The methods of use exemplified do not limit the invention, but provideguidance to the skilled artisan to use the compounds, compositions andmethods of the invention. The skilled practitioner will appreciate thatthe examples provide guidance and may be varied based on condition andthe patient.

Example A

A tablet composition for oral administration, according to the presentinvention, is made comprising: Component Amount The compound of Example9 15. mg Lactose 120. mg Maize Starch 70. mg Talc 4. mg MagnesiumStearate 1. mg(Other compounds having a structure according to Formula (I) are usedwith substantially similar results.)

A human female subject weighing 60 kg (132 lbs), suffering fromrheumatoid arthritis, is treated by a method of this invention.Specifically, for 2 years, a regimen of three tablets per day isadministered orally to said subject.

At the end of the treatment period, the patient is examined and is foundto have reduced inflammation, and improved mobility without concomitantpain.

Example B

A capsule for oral administration, according to the present invention,is made comprising: Component Amount (% w/w) The compound of Example 315% Polyethylene glycol 85%(Other compounds having a structure according to Formula (I) are usedwith substantially similar results.)

A human male subject weighing 90 kg (198 lbs), suffering fromosteoarthritis, is treated by a method of this invention. Specifically,for 5 years, a capsule containing 70 mg of the compound of Example 3 isadministered daily to said subject.

At the end of the treatment period, the patient is examined viaorthoscopy, and found to have no further advancement oferosion/fibrillation of the articular cartilage.

Example C

A saline-based composition for local administration, according to thepresent invention, is made comprising: Component Amount (% w/w) Thecompound of Example 13  5% Polyvinyl alcohol 15% Saline 80%(Other compounds having a structure according to Formula (I) are usedwith substantially similar results.)

A patient having deep corneal abrasion applies the drop to each eyetwice a day. Healing is speeded, with no visual sequelae.

Example D

A topical composition for local administration, according to the presentinvention, is made comprising: Component Composition (% w/v) Thecompound of Example 3 0.20 Benzalkonium chloride 0.02 Thimerosal 0.002d-Sorbitol 5.00 Glycine 0.35 Aromatics 0.075 Purified water q.s. Total =100.00(Other compounds having a structure according to Formula (I) are usedwith substantially similar results.)

A patient suffering from chemical burns applies the composition at eachdressing change (b.i.d.). Scarring is substantially diminished.

Example E

A inhalation aerosol composition, according to the present invention, ismade comprising: Component Composition (% w/v) Compound of Example 2 5.0Alcohol 33.0 Ascorbic acid 0.1 Menthol 0.1 Sodium Saccharin 0.2Propellant (F12, F114) q.s. Total = 100.0(Other compounds having a structure according to Formula (I) are usedwith substantially similar results.)

As asthma suffer sprays 0.01 mL via a pump actuator into the mouth whileinhaling. Asthma symptoms are diminished.

Example F

A topical opthalmic composition, according to the present invention, ismade comprising: Component Composition (% w/v) Compound of Example 50.10 Benzalkonium chloride 0.01 EDTA 0.05 Hydroxyethylcellulose(NATROSOL M) 0.50 Sodium metabisulfite 0.10 Sodium chloride (0.9%) q.s.Total = 100.0(Other compounds having a structure according to Formula (I) are usedwith substantially similar results.)

A human male subject weighing 90 kg (198 lbs), suffering from cornealulcerations, is treated by a method of this invention. Specifically, for2 months, a saline solution containing 10 mg of the compound of Example5 is administered to said subjects affected eye twice-daily.

Example G

A composition for parenteral administration is made comprising:Component Amount The compound of Example 4 100 mg/ml carrier Carrier:sodium citrate buffer with (percent by weight of carrier): lecithin0.48% carboxymethylcellulose 0.53 povidone 0.50 methyl paraben 0.11propyl paraben 0.011

The above ingredients are mixed, forming a suspension. Approximately 2.0ml of the suspension is administered, via injection, to a human subjectwith a premetastatic tumor. The injection site juxtaposes the tumor.This dosage is repeated twice daily, for approximately 30 days. After 30days, symptoms of the disease subside, and dosage is gradually decreasedto maintain the patient.

(Other compounds having a structure according to Formula I are used withsubstantially similar results.)

Example H

A mouthwash composition is prepared; Component % w/v The compound ofExample 1 3.00 SDA 40 Alcohol 8.00 Flavor 0.08 Emulsifier 0.08 SodiumFluoride 0.05 Glycerin 10.00 Sweetener 0.02 Benzoic acid 0.05 Sodiumhydroxide 0.20 Dye 0.04 Water balance to 100%

A patient with gum disease uses 1 ml of the mouthwash thrice daily toprevent further oral degeneration.

(Other compounds having a structure according to Formula I are used withsubstantially similar results.)

Example I

A lozenge composition is prepared; Component % w/v The compound ofExample 3 0.01 Sorbitol 17.50 Mannitol 17.50 Starch 13.60 Sweetener 1.20Flavor 11.70 Color 0.10 Corn Syrup balance to 100%

A patient uses the loosening to prevent loosening of an implant in themaxilla. (Other compounds having a structure according to Formula I areused with substantially similar results.)

Example J Chewing Gum Composition

Component w/v % The compound of Example 1 0.03 Sorbitol crystals 38.44Paloja-T gum base* 20.00 Sorbitol (70% aqueous solution) 22.00 Mannitol10.00 Glycerine 7.56 Flavor 1.00

A patient chews the gum to prevent loosening of dentures.

(Other compounds having a structure according to Formula I are used withsubstantially similar results.)

Example K

Components w/v % Compound of example 25 4.0 USP Water 50.656Methylparaben 0.05 Propylparaben 0.01 Xanthan Gum 0.12 Guar Gum 0.09Calcium carbonate 12.38 Antifoam 1.27 Sucrose 15.0 Sorbitol 11.0Glycerin 5.0 Benzyl Alcohol 0.2 Citric Acid 0.15 Coolant 0.00888 Flavor0.0645 Colorant 0.0014

The composition is prepared by first mixing 80 kg of gylcerin and all ofthe benzyl alcohol and heating to 65 C, then slowly adding and mixingtogether methylparaben, propylparaben, water, xanthan gum, and guar gum.Mix these ingredients for about 12 minutes with a Silverson in-linemixer. Then slowly add in the following ingredients in the followingorder: remaining glycerin, sorbitol, antifoam C, calcium carbonate,citric acid, and sucrose. Separately combine flavors and coolants andthen slowly add to the other ingredients. Mix for about 40 minutes.

The patient takes the formulation to prevent flare up of colitis.

All references described herein are hereby incorporated by reference.

While particular embodiments of the subject invention have beendescribed, it will be obvious to those skilled in the art that variouschanges and modifications of the subject invention can be made withoutdeparting from the spirit and scope of the invention. It is intended tocover, in the appended claims, all such modifications that are withinthe scope of this invention.

1-28. (canceled)
 29. A pharmaceutical composition comprising: (a) apharmaceutically-acceptable carrier; (b) a safe and effective amount ofa compound having a structure according to Formula (I):

wherein: A is alkyl, heteroalkyl, aryl or heteroaryl, substituted orunsubstituted; R₁ is NHOR₂, where R₂ is hydrogen or alkyl; W is one ormore of hydrogen; lower alkyl; or an alkylene bridge; Y is independentlyone or more of hydroxy, SR₃, SOR₄, SO₂R₈, alkoxy, or amino, whereinamino is of formula NR₆R₇, wherein R₆ and R₇ are independently chosenfrom hydrogen, alkyl, heteroalkyl, heteroaryl, aryl, OR₃, SO₂R₈, COR₉,CSR₁₀, and PO(R₁₁)₂; or R₆ and R₇ may join together to form a ring; R₃is hydrogen, alkyl, aryl, or heteroaryl; R₄ is alkyl, aryl, orheteroaryl; each R₈ is independently alkyl, aryl, heteroaryl,heteroalkyl, amino, alkylamino, dialkylamino, arylamino, diarylamino, oralkylarylamino; R₉ is hydrogen, alkoxy, aryloxy, heteroaryloxy, alkyl,aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino,arylamino, or alkylarylamino; R₁₀ is alkyl, aryl, heteroaryl,heteroalkyl, amino, alkylamino, dialkylamino, arylamino, diarylamino, oralkylarylamino; R₁₁ is alkyl, aryl, heteroaryl, or heteroalkyl; Z ishydrogen; hydroxy; alkyl; or an alkylene, or heteroalkylene; and n is 2;or an optical isomer, diastereomer or enantiomer of Formula (I), or apharmaceutically-acceptable salt, or biohydrolyzable amide, ester, orimide thereof.
 30. A composition according to claim 29, wherein saidcompound is selected from the group consisting of:(2R)-N,4-dihydroxy-1-(4-methoxyphenylsulfonyl)piperidine-2-carboxamide;(2R)-1-(4-bromophenylsulfonyl)-N,4-dihydroxypiperidine-2-carboxamide;(2R)-N-hydroxy-1-(4-methoxyphenylsulfonyl)-4-(phenylthio)piperidine-2-carboxamide;and(R)-N-hydroxy-4,4-dimethoxy-1-(4-methoxyphenylsulfonyl)piperidine-2-carboxamide.31. A composition according to claim 29, wherein said composition isformulated for an administration route selected from the groupconsisting of oral, rectal, topical, nasal, ocular, and parenteral. 32.A composition according to claim 29, wherein said composition isformulated for oral administration, said formulation being a chewinggum.